Tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them

ABSTRACT

A compound of Formula (Ih)The compounds may be used, inter alia, for preparing beta aryl-alpha-oxy substituted alkylcarboxylic acids.

This application is a divisional of application Ser. No. 09/257,104,filed Feb. 24, 1999, now U.S. Pat. No. 6,440,961, which in turn is acontinuation-in-part of application Ser. No. 09/012,585, filed Jan. 23,1998, now U.S. Pat. No. 6,054,453.

FIELD OF THE INVENTION

The present invention relates to novel hypolipidemic, antihyperglycemic,antiobesity and hypocholesterolemic compounds, their derivatives, theiranalogs, their tautomeric forms their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutically acceptable compositionscontaining these. More particularly, the present invention relates tonovel β-aryl-α-oxysubstituted alkylcarboxylic acids of the generalformula (I), their derivatives, their analogs. Their tautomeric forms,their stereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates and pharmaceuticallycompositions containing them.

The present invention also relates to a process for the preparation ofthe above said novel compounds, their analogs, their derivatives, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, pharmaceutically acceptable solvatesand pharmaceutical compositions containing them.

The present invention also relates to novel intermediates, processes fortheir preparation and their use in the preparation of compounds offormula (I).

The compounds of the present invention lower plasma glucose,triglycerides, total cholesterol (TC); increase high density lipoprotein(HDL) and decrease low density lipoprotein (LDL), which have beneficialeffects on coronary heart disease and atherosclerosis.

The compounds of general formula (I) are useful in reducing body weightand for the treatment and/or prophylaxis of diseases such ashypertension, coronary heart disease, atherosclerosis, stroke,peripheral vascular diseases and related disorders. These compounds areuseful for the treatment of familial hypercholesterolemia,hypertriglycaridemia, lowering of atherogenic lipoproteins, VLDL andLDL. The compounds of the present invention can be used for thetreatment of certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,retinopathy and nephropathy. The compounds of general formula (I) arealso useful for the treatment and/or prophylaxis of insulin resistance(type II diabetes), leptin resistance, impaired glucose tolerance,dyslipidemia and disorders related to syndrome X such as hypertension,obesity, insulin resistance, coronary heart disease, and othercardiovascular disorders. These compounds may also be useful as aldosereductase inhibitors, for improving cognitive functions in dementia,treating diabetic complications, disorders related to endothelial cellactivation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatorybowel diseases, osteoporosis, myotonic dystrophy, pancreatitis,arteriosclerosis, xanthoma, inflammation and for the treatment ofcancer. The compounds of the present inventions are useful in thetreatment and/or prophylaxis of the above said diseases iscombination/concomitant with one or more HMG CoA reductase inhibitors,hypolipidemic/hypolipoproteinemic agents such as fibric acidderivatives, nicotinic acid, cholestyramine, colestipol, probucol.

BACKGROUND OF INVENTION

Atherosclerosis and other peripheral vascular diseases are the majorcauses affecting the quality of life of millions of people. Therefore,considerable attention has been directed towards understanding theetiology of hypercholesterolemia and hyperlipidemia and development ofeffective therapeutic strategies.

Hypercholesterolemia has been defined as plasma cholesterol level thatexceeds an arbitrarily defined value called “normal” level. Recently, ithas been accepted that “ideal” plasma levels of cholesterol are muchbelow the “normal” level of cholesterol in general population and therisk of coronary artery disease (CAD) increases as cholesterol levelrises above the “optimum” (or “ideal”) value. There is clearly adefinite cause and effect-relationship between hypercholesterolemia andCAD, particularly for individuals with multiple risk factors. Most ofthe cholesterol in present in the esterified forms with variouslipoproteins such as Low density lipoprotein (LDL), Intermediate densitylipoprotein (IDL), High density lipoprotein (HDL) and partially as Verylow density lipoprotein (VLDL). Studies clearly indicate that there isan inverse correlationship between CAD and atherosclerosis with serumHDL-cholesterol concentrations. (Stampfer et al., N. Engl. J. Med., 325(1991), 373-381) and the risk of CAD increases with increasing levels ofLDL and VLDL.

In CAD, generally “fatty streaks” in carotid, coronary and cerebralarteries, are found which are primarily free and esterified cholesterol.Miller et al., (Br. Med. J., 282 (1981), 1741-1744) have shown thatincrease is HDL-particles may decrease the number of sites of stenosisin coronary arteries of human, and high level of HDL-cholesterol mayprotect against the progression of atherosclerosis. Picardo et al.,(Arteriosclerosis 6 (1986) 434-441) have shown by in vitro experimentthat HDL in capable of removing cholesterol from cells. They suggestthat HDL may deplete tissues of excess free cholesterol and transfer itto the liver (MaciKinnon et al., J. Biol. Chem. 261 (1986), 2548-2552).Therefore, agents that increase HDL cholesterol would have therapeuticsignificance for the treatment of hypercholesterolemia and coronaryheart diseases (CHD).

Obesity is a disease highly prevalent is affluent societies and in thedeveloping world and is a major cause of morbidity and mortality. It isa state of excess body fat accumulation. The causes of obesity areunclear. It in believed to be of genetic origin or promoted by aninteraction between the genotype and environment. Irrespective of thecause, the, result is fat deposition due to imbalance between the energyintake versus energy expenditure. Dieting, exercise and appetitesuppression have been a part of obesity treatment. There is a need forefficient therapy to fight this disease since it may lead to coronaryheart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis,reduced fertility and many other psychological and social problems.

Diabetes and insulin resistance is yet another disease which severelyeffects the quality of life of a large population in the world. Insulinresistance in the diminished ability of insulin to exert its biologicalaction across a broad range of concentrations. In insulin resistance,the body secretes abnormally high amounts of insulin to compensate forthis defect; failing which, the plasma glucose concentration inevitablyrises and develops into diabetes. Among the developed countries,diabetes mellitus is a common problem and in associated with a varietyof abnormalities including obesity, hypertension, hyperlipidemia (J.Clin. Invest, (1985) 75: 809-817; N. Engl. J. Med. (1987) 317: 350-357;J. Clin Endocrinol. Metab., (1988) 66: 580-583; J. Clin. Invest., (1975)68: 957-969) and other rural complications (See Patent Application No.WO 95/21608). It is now increasingly being recognized that insulinresistance and relative hyperinsulinemia have a contributory role inobesity, hypertension, atherosclerosis and type 2 diabetes mellitus. Theassociation of insulin resistance with obesity, hypertension and anginahas been described as syndrome having insulin resistance as the centralpathogenic link-Syndrome-X.

Hyperlipidemia is the primary cause for cardiovascular (CVD) and otherperipheral vascular diseases. High risk of CVD is related to the higherLDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoproteinseen in hyperlipidemia. Patients having glucose intolerance/insulinresistance in addition to hyperlipidemia have higher risk of CVD.Numerous studies in the past have shown that lowering of plasmatriglycerides and total cholesterol, in particular LDL and VLDL andincreasing HDL cholesterol help is preventing cardiovascular diseases.

Peroxisome proliferator activated receptors (PPAR) ere members of thenuclear receptor super family. The gamma (γ) isoform of PPAR (PPARγ) hasbeen implicated in regulating differentiation of adipocytes(Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell,(1995) 83: 803-812), whereas the alpha (α) isoform of PPAR (PPARα)mediates fatty acid oxidation (Trend Endocrin. Metab., (1993) 4 :291-296) thereby resulting in reduction of circulating free fatty acidin plasma (Current Biol. (1995) is: 618-621). PPARα agonists have beenfound useful for the treatment of obesity (WO 97/36579). It has beenrecently disclosed that the hypolipidemic effect is enhanced when amolecule has both PPARα and PPARγ agonism activity and suggested to beuseful for the treatment syndrome X (WO 91/25042). Synergism between theinsulin sensitizer PPARγ agonist) and HMG CoA reductase inhibitor hasbeen observed which is useful for the treatment of atherosclerosis andxanthoma. (EP 0 753 298).

It is known that PPARγ plays an important role in adipocytedifferentiation (Cell. (1996) 87, 377-389). Ligand activation of PPAR issufficient to cause complete terminal differentiation (Cell, (1994)79,1147-1156) including cell cycle withdrawal. PPARγ is consistentlyexpressed in certain cells and activation of this nuclear receptor withPPARγ agonists would stimulate the terminal differentiation of adipocyteprecursors and cause morphological and molecular changes characteristicsof a more differentiated less malignant state (Molecular Cell, (1998),465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., (1997)94, 237-241) and inhibition of expression of prostate cancer tissue(Cancer Research (1998), 58; 3344-3352). This would be useful in thetreatment of certain types of cancer, which express PPARγ and could leadto a quite nontoxic chemotherapy.

Leptin resistance is a condition wherein the target cells are unable torespond to leptin signal. This may give rise to obesity due to excessfood intake and reduced energy expenditure and cause impaired glucosetolerance, type 2 diabetes, cardiovascular diseases and such otherinterrelated complications. Kallen et al (Proc. Natl. Acad. Sci., (1996)93, 5793-5796) have reported that insulin sensitizers which perhaps dueto their PPAR agonist expression and lower plasma leptin concentration.However, it has been recently disclosed that compounds having insulinsensitizing property also possess leptin sensitization activity. Theylower the circulating plasma leptin concentrations by improving thetarget cell response to leptin (WO 93/02159).

A few β-aryl-α-hydroxy propionic acids, their derivatives and theiranalogs have been reported to be useful in the treatment ofhyperglycemia, hyperlipidemia and hypercholesterolemia. Some of suchcompounds described in the prior art are outlined below

i) U.S. Pat. No. 5,306,726; WO 91/19702 disclose several3-aryl-2-hydroxypropionic acid derivatives of general formula (IIa) and(IIb) as hypolipidemic and hypoglycemic agents.

Examples of these compounds are shown in formula (IIc) and (IId)

ii) International Patent Applications, WO 95/03038 and WO 96/04260disclose compounds of formula (IIe)

wherein R^(a) represents 2-benzoxazolyl or 2-pyridyl and R^(b) representCF₃, CH₂OCH₃ or CH₃. A typical example in(S)-3-[4-[2-[N-(2-benzoxazoly]-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoicacid (IIf).

iii) International Patent Application Nos. WO 94/13650, WO 94/01420 andWO 95/17394 disclose the compounds of general formula (IIg)

A¹—X—(CH₂)_(n)—O—A²—A³—Y.R  (IIg)

wherein A¹ represent aromatic heterocycle, A² represents substitutedbenzene ring and A³ represents moiety of formula (CH₂)_(m)—CH—(OR¹),wherein R¹ represents alkyl groups m is an integer of 1 to 5; Xrepresents substituted or unsubstituted N; Y represents C═O or C═S. R²represents OR³ where R³ in alkyl, aralkyl or aryl group and a in integeris the range of 2-6. An example of these compounds is shown is formula(IIh)

SUMMARY OF THE INVENTION

With an objective to develop novel compounds for the treatment and/orprophylaxis of diseases related to increased levels of lipids,atherosclerosis, coronary artery diseases especially to treathypertriglyceridemia and to lower free fatty acids, for the treatmentand/or prophylaxis of diseases described as Syndrome-X which includehyperlipidemia, hyperinsulinemia, obesity, insulin resistance, insulinresistance leading to type 2 diabetes acid diabetes complicationsthereof, for the treatment of diseases wherein insulin resistance in thepathophysiological mechanism, for the treatment of hypertension,atherosclerosis and coronary artery diseases with better efficacy,potency and lower toxicity, we focused our research to develop newcompounds effective in the treatment of above mentioned diseases. Effortin this direction has led to compounds having general formula (I).

The main objective of the present invention is therefore, to providenovel β-aryl-α-oxysubstituted alkylcarboxylic acids and theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them, or their mixtures.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkylcarboxylic acids and their derivatives,their analogs, their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them or their mixtures which may have agonist activityagainst PPARα and/or PPARγ and optionally inhibit HMG CoA reductase, isaddition to agonist activity against PPARα and/or PPARγ.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkylcarboxylic -acids and their derivatives,their analogs their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them or their mixtures having enhanced activities, withouttoxic effect or with, reduced toxic effect.

Yet another objective of the present invention is to produce a processfor the preparation of novel β-aryl-α-oxysubstituted alkylcarboxylicacids and them derivatives of the formula (I) as defined above, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts and their pharmaceuticallyacceptable solvates.

Still another objective of the present invention is to providepharmaceutical compositions containing compounds of the general formula(I), their analogs, their derivatives, their tautomers, theirstereoisomers, their polymorphs, their salts, solvates or them mixturesin combination with suitable carriers, solvents, diluents and othermedia normally employed in preparing such compositions.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to compounds having the general formula(I)

where R¹, R², R³, R⁴ are same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, alkoxy. cycloalkoxy, aryl,aryloxy, aralkyl, aralkoxy, heterocyclyl, aryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, acidor its derivatives, or sulfonic acid or its derivatives; the ring Afused to the ring containing X and N represents a 5-6 membered cyclicstructure containing carbon atoms, which may optionally contain one ormore heteroatoms selected from oxygen, sulfur or nitrogen atoms, whichmay optionally be substituted; the ring A may be saturated or containone or more double bonds or may be aromatic; X represents a heteroatomselected from oxygen, sulfur or NR⁹ where R⁹ is hydrogen, alkyl, aryl,alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Arrepresents an unsubstituted of substituted divalent single or fusedaromatic or heterocyclic group; RS represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl or unsubstituted or substituted aralkylgroup or forms a bond together with the adjacent group R⁶; R⁶ representshydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl orunsubstituted or substituted aralkyl or R⁶ forms a bond together withR⁵; R⁷ represents hydrogen or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl alkylaminocarbonyl, arylaminocarbonyl,acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R⁸ representshydrogen or unsubstituted or substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkylgroups; Y represents oxygen or NR¹⁰, where R¹⁰ represents hydrogen,alkyl, aryl, hydroxyalkyl, aralkyl, heterocylcyl, heteroaryl orheteroaralkyl groups; R⁸ and R¹⁰ together may form a 5 or 6 memberedcyclic structure containing carbon atoms, which may optionally containone or more heteroatoms selected from oxygen, sulfur or nitrogen; n isan integer ranging from 1-4 and m is an integer 0 or 1.

Suitable groups represented by R¹-R⁴ include hydrogen, halogen atom suchas fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro,formyl; substituted or unsubstituted (C₁-C₁₂)alkyl group, especially,linear or branched (C₁-C₆)alkyl group such as methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, t-butyl, n-pentyl, isopentyl, hexyl andthe like; cyclo (C₃-C₆)alkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like, the cycloalkyl group may besubstituted; cyclo(C₃-C₆)alkoxy group such as cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, thecycloalkoxy group may be substituted; aryl group such as phenyl,naphthyl and the like, the aryl getup may be substituted; aralkyl suchas benzyl, phenethyl, C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, thearalkyl group may be substituted and the substituted aralkyl is a groupsuch as CH₃C₆H₄CH₂, Hal-C₆H₄CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and thelike; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl,benzofuryl and the like, the heteroaryl group may be substituted;heterocyclyl groups such as azidinyl, pyrrolidinyl, morpholinyl,piperidinyl, piperazinyl and the like, the heterocyclyl group may besubstituted; aralkoxy group such as (I), benzyloxy, phenethyloxy,naphthylamethyloxy, phenylpropyloxy and the like, the aralkoxy getup maybe substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl,oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may besubstituted; aralkylamino group such as C₆H₅CH₂NH, C₆H₅CH₂CH₂NH,C₆H₅CH₂NCH₃ and the like, which may be substituted; alkoxycarbonyl suchas methoxycarbonyl, ethoxycarbonyl and the like, the alkoxycarbonylgroup may substituted; aryloxycarbonyl group such as substituted orunsubstituted phenoxycarbonyl, naphthyloxycarbonyl and the like, thearyloxycarbonyl group may be substituted; aralkoxycarbonyl group such asbenzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and thelike, which may be substituted; monoalkylamino group such as NNCH₃,NHC₂H₅, NHC₃H₇, NHC₆H₁₃ and the like, which may be substituted;dialkylamino group such as N(CH₃)₂, NCH₃(C₂H₅) and the like, which maybe substituted; alkoxyalkyl group such as methoxymethyl, ethoxymethyl,methoxyethyl, ethoxyethyl and the like, the alkoxyalkyl group may besubstituted; aryloxyalkyl group such as C₆H₅OCH₂, C₆H₅OCH₂CH₂,naphthyloxymethyl and the like, which may be substituted; aralkoxyalkylgroup such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂ and the like, which may besubstituted; heteroaryloxy and heteroaralkoxy, wherein heteroaryl andheteroaralkyl moieties are as defined earlier and may be substituted;aryloxy group such as phenoxy, naphthyloxy and the like, the aryloxygroup may be substituted; arylamino group such as HNC₆H₅, NCH₃(C₆H₅),NHC₆H₄CH₃, NHC₆H₄-Hal and the like, the arylamino group may besubstituted amino, group; amino (C₁-C₆)alkyl, which may be substituted;hydroxy(C₁-C₆)alkyl, which may be substituted; (C₁-C₆)alkoxy such asmethoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, whichmay be substituted; thio(C₁-C₆)alkyl, which may be substituted;(C₁-C₆)alkylthio, which may be substituted; acyl group such as acetyl,propionyl, benzoyl and the like, the acyl group may be substituted;acylamino groups such as NHCOCH₃, NHCOC₂H₅, NHCOC₃H₇, NHCOC₆H₅ and thelike, which may be substituted; aralkoxycarbonylamino group such asNHCOOCH₂C₆H₅, NHCOOCH₂CH₂C₆H₅, N(CH₃)COOCH₂C₆H₅, N(₂H₅)COOCH₂C₆H₅,NHCOOCH₂C₆H₄CH₃, NHCOOCH₂C₆H₄OCH₃ and the like, thearalkoxycarbonylamino group may be substituted; aryloxycarbonylaminogroup such as NHCOOC₆H₅, NHCOOC₆H₅, NCHOOC₆H₅, NC₂H₅COOC₆H₅,NCHCOOC₆H₄CH₃, NHCOOC₆H₄OCH₃ and the like, the aryloxycarbonylaminogroup may be substituted; alkoxycarbonylamino group such as NHCOOc₂H₅,NHCOOCH₃ and the like, the alkoxycarbonylamino group may be substituted;carboxylic acid or its derivatives such as amides, like CONH₂, CONHMe,CONMe₂, CONMEt, CONEt₂, CONHPh and the like, the carboxylic acidderivatives may be substituted; acyloxy group such as OOCMe, OOCEt,OOCPh and the like which may optionally be substituted; sulfonic acid orits derivatives such as SO₂NH₂, SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ and the like,the sulfonic acid derivatives may be substituted.

When the groups represented by R¹-R⁴ are substituted, the substituentsmaybe selected from halogen, hydroxy, or nitro or unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aralkyl, aralkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl,alkylamino, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives. These groups are asdefined above.

Suitable ring A includes phenyl, naphthyl, cyclohexyl, cyclohexenyl,thienyl, furyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl,isoxazolyl, pyridyl, pyranyl, dihydropyranyl, pyridazyl, pyrimidinyl andthe like; which may be unsubstituted or substituted and substituents areselected from the same group as that of R¹-R⁴ and are defined as theyare for R¹-R⁴. Preferred substituents are halogen, hydroxy, amino,formyl, optionally halogenated (C₁-C₆)alkyl, (C₁-C₆)alkoxy,cyclo(C₃-C₆)alkyl, cyclo(C₃-C₆)alkoxy, aryl, aralkyl, aralkoxy,heterocyclyl, acyl, acyloxy, carboxyl, alkoxycarbonyl, aralkoxycarbonyl,alkylamino, acylamino, aralkoxycarbonylamino or aminocarbonyl groups.

It is preferred that cyclic structure represented by ring A is a phenylor a pyridyl ring.

It is still more preferred that the cyclic s represented by ring A is aphenyl ring.

Suitable X includes oxygen, sulfur or a group NR⁹, preferably oxygen andsulfur. Suitably, R⁹ represents hydrogen, (C₁-C₆), (C₃-C₆) cycloalkyl,aralkyl a group such as benzyl, phenethyl; acyl getup such as acetyl,propanoyl, butanoyl, benzoyl and the like; (C₁-C₆)alkoxycarbonyl;aryloxycarbonyl such as phenoxycarbonyl, CH₃OC₆H₄OCO, Hal-C₆H₄OCO,CH₃C₆H₄OCO, naphthyloxycarbonyl and the like; aralkoxycarbonyl such asbenzyloxycarbonyl, phenethyloxycarbonyl and the like; the groupsrepresented by R⁹ may be substituted or unsubstituted. When the groupsrepresented by R⁹ are substituted, the substituents may be selected fromhalogen, optionally halogenated lower alkyl, hydroxy, optionallyhalogenated (C₁-C₃)alkoxy groups.

The group represented by Ar includes substituted or unsubstituted groupsselected from divalent phenylene, naphthylene, pyridyl, quinolinyl,benzofuryl, benzopyranyl, benzoxazolyl, benzothiazolyl, indolyl,indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl,dyhydrobenzopyranyl, pyrazolyl and the like. The substituents on thegroup represented by Ar include linear or branched optionallyhalogenated (C₁-C₆)alkyl, optionally halogenated (C₁-C₃)alkoxy, halogen,acyl, amino, acylamino, thio, carboxylic and sulfonic acids and theirderivatives. The substituents are defined as they are for R¹-R⁴.

It in more preferred that Ar represents a substituted or unsubstituteddivalent phenylene, naphthylene, benzofuranyl, indolyl, indolinyl,quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolylgroups.

It in still more preferred that Ar to divalent phenylene orbenzofuranyl, which may be unsubstituted or substituted by methyl,halomethyl, methoxy or halomethoxy groups.

Suitable R⁵ includes hydrogen, lower alkyl, groups such as methyl, ethylor propyl; hydroxy, (C₁-C₃)alkoxy; halogen atom such as fluorine,chlorine, bromine or iodine; aralkyl such as benzyl, phenethyl, whichmay be unsubstituted or substituted with halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, benzyloxy, acetyl, acetyloxy groups or R⁵ together withR⁶ represent a bond.

Suitable R⁶ may be hydrogen, lower alkyl, groups such as methyl, ethylor propyl; hydroxy, (C₁-C₃)alkoxy; halogen atom such as fluorine,chlorine, bromine or iodine; acyl group such as linear or branched(C₂-C₁₀)acyl group such as acetyl, propanoyl, butanoyl, pentanoyl,benzoyl and the like; aralkyl such as benzyl, phenethyl, which may beunsubstituted or substituted with halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, benzyloxy, acetyl, acetyloxy groups or together with R⁵;forms a bond.

It is preferred that R⁵; and R⁶ represent hydrogen atom or R⁵ and R⁶together represent a bond.

Suitable groups represented by R⁷ may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group such asmethyl, ethyl, n-propyl, iso-propyl, n butyl, iso-butyl, pentyl, hexyl,octyl and the like, the alkyl, group may be substituted;(C₁-C₇)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like, the cycloalkyl group may be substituted; arylgroup such as, phenyl, naphthyl, the aryl group may be substituted;heteroaryl group such as pyridyl, thienyl, furyl and the like, theheteroaryl group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; aralkyl group wherein thearyl group is an defined earlier and the alkyl, moiety may contain C₁-C₆atoms such as benzyl, phenethyl and the like, wherein the aralkyl groupmay be substituted; heterocyclyl group such as aziridinyl, pyrrolidinyl,piperidinyl and the like, the heterocyclyl group may be substituted;(C₁-C₆)alkoxy(C₁-C₆)alkyl group such as methoxymethyl, ethoxymethyl,methoxyethyl, ethoxypropyl and the like, the alkoxyalkyl group may besubstituted; acyl group such as acetyl, propanoyl, butanoyl, benzoyl andthe like, the acyl group may be substituted; (C₁-C₆) (alkoxycarbonylsuch as methoxycarbonyl, ethoxycarbonyl and the like, the alkoxycarbonylgroup may be substituted; aryloxycarbonyl such as phenoxycarbonyl,naphthyloxycarbonyl and the like, the arytoxycarbonyl group may besubstituted; (C₁-C₆)alkylaminocarbonyl, the alkyl group may besubstituted; arylaminocarbonyl such as PhNHCO, naphthylaminocarbonyl,the aryl moiety may be substituted. The substituents may be selectedfrom halogen, hydroxy, or vitro or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl acyl, acyloxy,hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy,aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl,alkylthio, thioalkyl groups, carboxylic acid or its derivatives, orsulfonic acid or its derivatives. These substituents are as definedabove.

Suitable groups represented by R⁸ may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group such asmethyl, ethyl, a propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl,octyl and the like; (C₃-C₇)cycloalkyl such as cyclopropyl, cyclopentyl,cyclohexyl and the like, the cycloalkyl group may be substituted; arylgroup such as phenyl, naphthyl, the aryl group may be substituted;heteroaryl group such as pyridyl, thienyl, furyl and the like, theheteroaryl group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; aralkyl group such asbenzyl, phenethyl and the like, the aralkyl group may be substituted;heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and thelike, the heterocyclyl group may be substituted, The substituents may beselected from halogen, hydroxy, formyl or vitro or unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl,acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl,aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl,aryloxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives. These substituents areas defined above.

Suitable groups represented by R¹⁰ may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl; preferably (C₁-C₁₂)alkyl;hydroxy(C₁-C₆)alkyl; aryl group such as phenyl, naphthyl and the like;aralkyl group such as benzyl, phenethyl and the like; heterocyclyl groupsuch as aziridinyl, pyrrolidinyl, piperidinyl, and the like; heteroarylgroup such as pyridyl, thienyl, furyl and the like; heteroaralkyl groupsuch as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and thelike.

Suitable ring structures formed by R⁸ and R¹⁰ together may be selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.

Suitable m in an integer ranging from 0-1. It is preferred that whenm=0, Ar represents a divalent benzofuranyl, benzoxazolyl,benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl,dyhydrobenzopyranyl groups, preferably benzofuranyl group and when m=1,Ar represents divalent phenylene, naphthylene, pyridyl, quinolinyl,benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl,azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl,dyhydrobenzopyranyl, pyrazolyl groups.

It is preferred that when m=0, Ar represents a divalent benzofuranylgroup, more preferably benzofuran-2,5-diyl group, and when m=1, Arrepresents a phenylene group.

Suitable n is an integer ranging from 1 to 4, preferably n represents aninteger 1 or 2.

It is preferred that when m=1, n represents 2.

It is also preferred that when m=0, n represents 1.

Pharmaceutically acceptable salts forming part of this invention includesalts of the carboxylic acid moiety such as alkali metal salts like Li,Na, and K salts; alkaline earth metal salts (I), Ca and Mg salts; saltsof organic bases such as diethanolamine, choline and the like; chiralbases like alkyl phenyl amine, phenyl glycinol and the like; naturalaminoacids such as lysine, arginine, guanidine, and the like; unnaturalaminoacids such as D-isomers or substituted aminoacids; ammonium orsubstituted ammonium salts and aluminum salts. Salts may include acidaddition salts where appropriate which are, sulphates, nitrates,phosphates, perchlorates, borates, hydrohalides, acetates, tartrates,maleates, citrates, palmoates, methanesulphonates, benzoates,salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates,glycerophosphates, ketoglutarates and the like. Pharmaceuticallyacceptable solvates may be hydrates or comprising other solvents ofcrystallization such as alcohols.

The pharmaceutically acceptable salts forming part of this invention arefound to have good solubility which is one of the essential propertiesfor pharmaceutical compounds.

Particularly useful compounds according to the present invention include

Ethyl(E/Z)-3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate;

Ethyl (E)-3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate;

Ethyl (Z)-3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate;

Ethyl(E/Z)-3-[2-(phenothiazin-10-yl)metlylbenzofuran-5-yl]-2-ethoxypropenoate;

Ethyl(E)-3-[2-(phenothiazin-10-yl)metlylbenzofuran-5-yl]-2-ethoxypropenoate;

Ethyl(Z)-3-[2-(phenothiazin-10-yl)metlylbenzofuran-5-yl]-2-ethoxypropenoate;

Ethyl(E/Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2ethoxypropenoate;

Ethyl(E)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2ethoxypropenoate;

Ethyl(Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2ethoxypropenoate;

(±)Methyl 3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate;

(+)Methyl 3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate;

(−)Methyl 3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate;

(±)Methyl3-[2-(phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;

(+)Methyl3-[2-(phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;

(−)Methyl3-[2-(phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;

(±)Methyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate;

(+)Methyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate;

(−)Methyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate;

(±)Ethyl 3-[4-(2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate;

(+)Ethyl 3-[4-(2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate;

(−)Ethyl 3-[4-(2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate;

(±)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(+)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(−)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(±)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoate;

(+)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoate;

(−)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoate;

(±)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoate;

(+)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoate;

(−)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoate;

(±)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate;

(+)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate;

(−)Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate;

(±)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid andits salts;

(+)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid andits salts;

(−)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid andits salts;

(±)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoicacid and its salts;

(+)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoicacid and its salts;

(−)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoicacid and its salts;

(±)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acidand its salts;

(+)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acidand its salts;

(−)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acidand its salts;

(±)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoicacid and its salts;

(+)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoicacid and its salts;

(−)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoicacid and its salts;

(±)3-[2-(Phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts;

(+)3-[2-(Phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts;

(−)3-[2-(Phenothiazin-10-yl)methylbenzofuran-5-yl]-

(±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid andits salts;

(+)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid andits salts;

(−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid andits salts;

(±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoicacid and its salts;

(+)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoicacid and its salts;

(−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoicacid and its salts;

(±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acid andits salts;

(+)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acid andits salts;

(−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acid andits salts;

(±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoicacid and its salts;

(+)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoicacid and its salts;

(−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoicacid and its salts;

(±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid andits salts;

(+)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid andits salts;

(−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid andits salts;

(±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoic acid andits salts;

(+)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoic acid andits salts;

(−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoic acid andits salts;

(±) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoic acidand its salts;

(+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoic acidand its salts;

(−) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoic acidand its salts;

(±) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acid andits salts;

(+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acid andits salts;

(−) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acid andits salts;

[(2R)-N(1S)]-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide;

[(2S)-N(1S)]-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide;

[(2S)-N(1S)]-3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide and

[(2R)-N(1S)]-3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide.

According to a feature of the present invention, the compound of generalformula (III) where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X, A, n, m, Ar areas defined earlier can be prepared by any of the following routes shownin Scheme I. The compound of general formula (III) represent a compoundof general formula (I), wherein all the symbols are as defined earlierand R⁵ and R⁶ together represent a bond and Y represents oxygen atom.

Route (1): The reaction of a compound of the general formula (IIIa)where all symbols are as defined earlier with a compound of formula(IIIb), where R¹¹ may be a lower alkyl group and R⁷ and R⁸ are asdefined earlier excluding hydrogen, to yield a compound of generalformula (III) may be carried out in the presence of a base such asalkali metal hydrides like NaH, KH or organolithiums like CH₃Li, BuLiand the like or alkoxides such as NaOMe, NaOEt, K⁺BuO⁻ or mixturesthereof. The reaction may be carried out in presence of solvents such asTHF, dioxane, DMF, DMSO, DME and the like or mixture thereof. HMPA maybe used as cosolvent. The reaction temperature may range from −78° C. to50° C., preferably at a temperature in the range of −10° C. to 30° C.The compound of general formula (III b) may be prepared according to theprocedure described in the literature (Annalen. Chemie, (1996) 53, 699).

Alternatively, the compound of formula (III) may be prepared by reactingthe compound of formula (IIIa) where all symbols are as defined earlierwith Wittig reagents such as Hal⁻ PH₃P⁺CH—(OR⁷)CO₂R⁸ under similarreaction conditions as described above.

Route (2): The reaction of a compound of the general formula (IIIa)where all symbols are as defined earlier with a compound of formula(IIIc) where R⁶ represents a hydrogen atom and R⁷ and R⁸ are as definedearlier may be carried out in the presence of a base. The base is notcritical. Any base normally employed for aldol condensation reaction maybe employed; bases like metal hydride such as NaH, KH, metal alkoxidessuch as NaOMe, K⁺BuO⁻, NaOEt, metal amides such as LiNH₂, LiN(ipr)₂ maybe used. Aprotic solvent such as THF, ether, dioxane may be used. Thereaction may be carried out in an inert atmosphere which may bemaintained by using inert gases such as N₂, Ar, or He and the reactionis more effective under anhydrous conditions. Temperature in the rangeof −80° C. to 35° C. may be used. The β-hydroxy product initiallyproduced may be dehydrated under conventional dehydration conditionssuch as treating with PTSA in solvents such as benzene or toluene. Thenature of solvent and dehydrating agent is not critical. Temperature inthe range of 20° C. to reflux temperature of the solvent used may beemployed, preferably at reflux temperature of the solvent by continuousremoval of water using a Dean Stark water separator.

Route (3): The reaction of compound of formula (IIIe) where L¹ is aleaving group such as halogen atom, p-toluenesulfonate,methanesulfonate, trifluoromethanesulfonate and the like and all symbolsare as defined earlier with a compound of formula (IIId) where R⁷, R⁸and Ar are as defined earlier to produce a compound of the formula (III)may be carried out in the presence of solvents such as THF, DMF, DMSO,DME and the like or mixtures thereof. The reaction may be carried out inan inert atmosphere which may be maintained by using inert gases such asNi₂, Ar, or He. The reaction may be effected in the presence of a basesuch as K₂CO₃, Na₂CO₃ or NaH or mixtures thereof. Acetone may be used assolvent when Na₂CO₃ or K₂CO₃ is used as a base. The reaction temperaturemay range from 0° C.-120° C., preferably at a temperature in the rangeof 30° C.-100° C. The duration of the reaction may range from 1 to 24hours, preferably from 2 to 12 hours. The compound of formula (IIId) canbe prepared according to known procedure by a Wittig Horner reactionbetween the protected hydroxy aryl aldehyde such as benzyloxyarylaldehyde and compound of formula (IIIb), followed by reduction of doubleblood and deprotection.

Route (4): The reaction of a compound of general formula (IIIg) whereall symbols are as defined earlier with a compound of general formula(IIIf) where all symbols are as defined earlier and L¹ is a leavinggroup such as halogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate and the like, preferably a halogen atom toproduce a compound of general formula (III) may be carried out in thepresence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and thelike or a combination thereof. The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar, He. The reaction may be effected in the presence of a base suchas alkalis like sodium hydroxide, potassium hydroxide and the like,alkali metal carbonate like sodium carbonate, potassium carbonate andthe like; alkali metal hydrides such as sodium hydride, potassiumhydride and the like; organometallic bases like n-butyl lithium, alkalimetal amides like sodamide or mixtures thereof. The amount of base mayrange from 1 to 5 equivalents, based on the amount of the compound offormula (IIIg), preferably the amount of base ranges from 1 to 3equivalents. Phase transfer catalysts such as tetraalkylammonium halideor hydroxide may be added. The reaction may be carried out at atemperature in the range of 0° C. to 150° C., preferably at atemperature in the range of 15° C. to 100° C. The duration of thereaction may range from 0.25 to 48 hours, preferably from 0.25 to 12hours.

Route (5): The reaction of compound of general formula (IIIh) where allsymbols are as defined earlier with a compound of general formula (IIId)where all symbols are as defined above may be carried out using suitablecoupling agents such as dicyclohexyl urea,triarylphosphine/dialkylazadicarboxylate such as PPh₃/DEAD and the like.The reaction may be carried out in the presence of solvents such as THF,DME, CH₂Cl₂, CHCl₃, toluene, acetronitrile, carbontetrachloride and thelike. The inert atmosphere may be maintained by using inert gases suchas N₂, Ar, He. The reaction may be effected in the presence of DMAP,HOBT and they may be used in the range of 0.05 to 2 equivalents,preferably 0.25 to 1 equivalents. The reaction temperature may be in therange of 0° C. to 100° C., preferably at a temperature in the range of20° C. to 80° C. The duration of the reaction may range from 0.5 to 24hours, preferably from 6 to 12 hours.

Route 6: The reaction of a compound of formula (IIIi) where all symbolsare as defined earlier with a compound of formula (IIIj) where R⁷=R⁸ andare as defined earlier excluding hydrogen, to produce a compound of theformula (III) where all symbols are as defined earlier may be carriedout neat in the presence of a base such as alkali metal hydrides likeNaH or KH or organolithiums like CH₃Li, BuLi and the like or alkoxidessuch as NaOMe, NaOEt, K⁺BuO⁻ and the like or mixtures thereof. Thereaction may be carried out in the presence of aprotic solvents such asTHF, dioxane, DMF, DMSO, DME and the like or mixture thereof. HMPA maybe used as cosolvent. The reaction temperature may range from −78° C. to100° C., preferably at a temperature in the range of −10° C. to 50° C.

According to another embodiment of the present invention, the compoundof the general formula (I) where R⁵ represents hydroxy, alkoxy, halogen,lower alkyl or unsubstituted or substituted aralkyl group, R⁶ representshydroxy, alkoxy, halogen, lower alkyl group, acyl or unsubstituted orsubstituted aralkyl group, R¹, R², R³, R⁴, R⁷, R⁸, X, A, n, m, Ar asdefined earlier and Y represents oxygen atom can be prepared by one ormore of the processes shown in Scheme-II:

Route (7): The reduction of compound of formula (III) which represents acompound of formula (I) where R⁵ and R⁶ together represent a bond and Yrepresents an oxygen atom and all other symbols are as defined above maybe obtained as described earlier in Scheme-I, to yield a compound of thegeneral formula (I) where R⁵ and R⁶ each represent hydrogen atom and allsymbols are as defined earlier, may be carried out in the presence ofgaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the like.Mixtures of catalysts may be used. The reaction may also be conducted inthe presence of solvents such as dioxane, acetic acid, ethyl acetate,ethanol and the like. The nature of the solvent is not critical. Apressure between atmospheric pressure and 80 psi may be employed. Higherpressures may be used to reduce the reaction time. The catalyst may bepreferably 5-10% Pd/C and the amount of catalyst used may range from1-100% w/w. The reaction may also be carried out by employing metalsolvent reduction such as magnesium in alcohol or sodium amalgam inalcohol. The hydrogenation may be carried out in the presence of metalcatalysts containing chiral ligands to obtain a compound of formula (I)in optically active form. The metal catalyst may contain Rhodium,Ruthenium, Indium and the like. The chiral ligands may preferably bechiral phosphines such as (2S,3S)-bis(diphenylphosphino)butane,1,2-bis(diphenylphosphino)ethane,1,2-bis(2-methoxyphenylphosphino)ethane,(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenyl phosphino)butaneand the like. Any suitable chiral catalyst may be employed which wouldgive required optical purity of the product (I) (Ref: Principles ofAsymmetric Synthesis, Tet. Org. Chem. Series Vol 14, pp311-316, Ed.Baldwin J. E.).

Route (8): The reaction of compound of formula (Ia) where R⁸ is asdefined earlier excluding hydrogen and all other symbols are as definedearlier and L³ is a leaving group such as halogen atom with an alcoholof general formula (Ib), where R⁷ is as defined earlier excludinghydrogen to produce a compound of the formula (I) may be carried out inthe presence of solvents such as THF, DMF, DMSO, DME and the like ormixtures thereof. The reaction may be carried out in an inert atmospherewhich may be maintained by using inert gases such as N₂, Ar, or He. Thereaction may be effected in the presence of a base such as KOH, NaOH,NaOMe, NaOEt, K⁺BuO⁻ or NaH or mixtures thereof. Phase transfercatalysts such as tetraalkylammonium halides or hydroxides may beemployed. The reaction temperature may range from 20° C.-120° C.,preferably at a temperature in the range of 30° C.-100° C. The durationof the reaction may range from 1 to 12 hours, preferably from 2 to 6hours. The compound of formula (Ia) may be prepared according to theprocess disclosed in our copending application Ser. No. 08/982,910.

Route (9): The reaction of compound of formula (IIIe) defined earlierwith compound of formula (Ic) where all symbols are as defined earlierto produce a compound of the formula (I) may be carried out in thepresence of solvents such as THF, DMF, DMSO, DME and the like ormixtures theroef. The reaction may be carried out in an inert atmospherewhich is maintained by using inert gases such as N₂, Ar or He. Thereaction may be effected in the presence of a base such as K₂CO₃, Na₂CO₃or NaH or mixtures thereof. Acetone may be used as a solvent when K₂CO₃or Na₂CO₃ is used as a base. The reaction temperature may range from 20°C.-120° C., preferably at a temperature in the range of 30° C.-80° C.The duration of the reaction may range from 1 to 24 hours, preferablyfrom 2 to 12 hours. The compound of formula (Ic) may be prepared byWittig Horner reaction between the protected hydroxyaryl aldehyde andcompound of formula (IIIb) followed by reduction of the double bond anddeprotection. Alternatively, the compound of formula (Ic) may beprepared by following a procedure disclosed in WO 94/01420.

Routine (10): The reaction of compound of general formula (IIIh) definedearlier with a compound of general formula (Ic) where all symbols are asdefined earlier may be carried out using suitable coupling agents suchas dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such asPPh₃/DEAD and the like. The reaction may be carried out in the presenceof solvents such as THF, DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile,carbontetrachloride and the like. The inert atmosphere may be maintainedby using inert gases such as N₂, Ar or He. The reaction may be effectedin the presence of DMAP, HOBT and they may be used in the range of 0.05to 2 equivalents, preferably 0.25 to 1 equivalents. The reactiontemperature may be in the range of 0° C. to 100° C., preferably at atemperature in the range of 20° C. to 80° C. The duration of thereaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.

Route (11): The reaction of compound of formula (Id), which represents acompound of formula (I) where all symbols are as defined earlier, with acompound of formula (Ie) where R⁷ represents unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxylated, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkylgroups and Hal represents Cl, Br, or I, to produce a compound of formula(I) may be carried out in the presence of solvents such as THF, DMF,DMSO, DME and the like. The inert atmosphere may be maintained by usinginert gases such as N₂, Ar or He. The reaction may be effected in thepresence of a base such as KOH, NaOH, NaOMe, K⁺BuO⁻, NaH and the like.Phase transfer catalyst such as tetraalkylammonium halides or hydroxidesmay be employed. The reaction temperature may range from 20° C. to 150°C., preferably at a temperature in the range of 30° C. to 100° C. Theduration of the reaction may range from 1 to 24 hours, preferably from 2to 12 hours. The compound of formula (Id) represents compound of formula(I) where R⁷ represents H and Y represents oxygen atom.

Route (12): The reaction of a compound of the general formula (IIIa)defined earlier with a compound of formula (IIIc) where R⁶, R⁷ and R⁸are as defined earlier may be carried out under conventional conditions.The base is not critical. Any base normally employed for aldolcondensation reaction may be employed, like, metal hydrides such as NaH,KH and the like, metal alkoxides such as NaOMe, K⁺BuO⁻, NaOEt and thelike, metal amides such as LiNH₂, LiN(ipr)₂ and the like. Aproticsolvents such as THF, ethers, dioxane may be used. The reaction may becarried out in an inert atmosphere which may be maintained by usinginert gases such as N₂, Ar, or He and the reaction is more effectiveunder anhydrous conditions. Temperature in the range of −80° C. to 25°C. may be used. The β-hydroxy aldol product may be dehydroxylated usingconventional methods, conveniently by ionic hydrogenation technique suchas by treating with a trialkyl silane in the presence of an acid such astrifluoroacetic acid. Solvent such as CH₂Cl₂ may be used. Favorably,reaction proceeds at 25° C. Higher temperature may be employed if thereaction is slow.

Route (13): The reaction of a compound of general formula (IIIg) whereall symbols are as defined earlier with a compound of general formula(If) where L¹ is a leaving group such as halogen atom,p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and thelike, preferably a halogen atom and all other symbols are as definedearlier to produce a compound of general formula (I) may be carried outin the presence of solvents such as DMSO, DMF, DME, THF, dioxane, etherand the like or a combination thereof. The reaction may be carried outin an inert atmosphere which may be maintained by using inert gases suchas N₂, Ar or He. The reaction may be effected in the presence of a basesuch as alkalis like sodium hydroxide, potassium hydroxide and the like,alkali metal carbonates like sodium carbonate, potassium carbonate andthe like; alkali metal hydrides such as sodium hydride, potassiumhydride and the like; organometallic bases like n-butyl lithium, alkalimetal amides like sodamide or mixtures thereof. The amount of base mayrange from 1 to 5 equivalents, based on the amount of the compound offormula (IIIg), preferably the amount of base ranges from 1 to 3equivalents. The reaction may be carried out in the presence of phasetransfer catalysts such as tetraalkylammonium halides or hydroxides. Thereaction may be carried out at a temperature in the range of 0° C. to150° C., preferably at a temperature in the range of 15° C. to 100° C.The duration of the reaction may range from 0.25 to 24 hours, preferablyfrom 0.25 to 12 hours.

Route 14: The conversion of compound of formula (Ig) where all symbolsare as defined earlier to a compound of formula (I) where all symbolsare as defined earlier may be carried out either in the presence of baseor acid and the selection of base or acid is not critical. Any basenormally used for hydrolysis of nitrile to acid may be employed, metalhydroxides such as NaOH or KOH in an aqueous solvent or any acidnormally used for hydrolysis of nitrile to ester may be employed such asdry HCl in an excess of alcohol such as methanol, ethanol, propanol andthe like. The reaction may be carried out at a temperature in the rangeof 0° C. to reflux temperature of the solvent used, preferably at atemperature in the range of 25° C. to reflux temperature of the solventused. The duration of the reaction may range from 0.25 to 48 hrs.

Route 15: The reaction of a compound of formula (Ih) where R⁸ is asdefined earlier excluding hydrogen all symbols are as defined earlierwith a compound of formula (Ib) where R⁷ is as defined earlier excludinghydrogen to produce a compound of formula (I) (by a rhodium carbenoidmediated insertion reaction) may be carried out in the presence ofrhodium (II) salts such as rhodium (II) acetate. The reaction may becarried out in the presence of solvents such as benzene, toluene,dioxane, ether, THF and the like or a combination thereof or whenpracticable in the presence of R⁷OH as solvent at any temperatureproviding a convenient rate of formation of the required product,generally at an elevated temperature, such as reflux temperature of thesolvent. The inert atmosphere may be maintained by using inert gasessuch as N₂, Ar or He. The duration of the reaction may range from 0.5 to24 h, preferably from 0.5 to 6 h.

The compound of formula (I) where R⁸ represents hydrogen atom may beprepared by hydrolysis using conventional methods, a compound of formula(I) where R⁸ represents all groups defined earlier except hydrogen. Thehydrolysis may be carried out in the presence of a base such as Na₂CO₃and a suitable solvent such as methanol, ethanol and the like ormixtures thereof. The reaction may be carried out at a temperature inthe range of 20° C.-40° C., preferably at 25° C.-30° C. the reactiontime may range from 2 to 12 h, preferably from 4 to 8 h.

The compound of general formula (I) where Y represents oxygen and R⁸represents hydrogen or lower alkyl groups and all other symbols are asdefined earlier may be converted to compound of formula (I), where Yrepresents NR¹⁰ by reaction with appropriate amines of the formulaNHR⁸R¹⁰ where R⁸ and R¹⁰ are as defined earlier. Alternatively, thecompound of formula (I) where YR⁸ represents OH may be converted to acidhalide, preferably YR⁸═Cl, by reacting with appropriate reagents such asoxalyl chloride, thionyl chloride and the like, followed by treatmentwith amines of the formula NHR⁸R¹⁰ where R⁸ and R¹⁰ are as definedearlier. Alternatively, mixed anhydrides may be prepared from compoundof formula (I) where YR⁸ represents OH and all other symbols are asdefined earlier by treating with acid halides such acetyl chloride,acetyl bromide, pivaloyl chloride, dichlorobenzyl chloride and the like.The reaction may be carried out in the presence of suitable base such aspyridine, triethylamine, diisopropyl ethyl amine and the like. Solventssuch as halogenated hydrocarbons like CHCl₃, CH₂Cl₂, hydrocarbons suchas benzene, toluene, xylene and the like may be used. The reaction maybe carried out at a temperature in the range of −40° C. to 40° C.,preferably 0° C. to 20° C. The acid halide or mixed anhydride thusprepared may further be treated with appropriate amines of the formulaNHR⁸R¹⁰ where R⁸ and R¹⁰ are as defined earlier.

The processes for the preparation of compounds of general formula (IIIa)have been described in a copending application Ser. No. 08/982,910.

As used herein the term neat means the reaction is carried out withoutthe use of solvent.

In another embodiment of the present invention the novel intermediate offormula (If)

where Ar represents an unsubstituted or substituted divalent single orfused aromatic or heterocyclic group; R⁵ represents hydrogen atom,hydroxy, alkoxy, halogen, lower alkyl or unsubstituted or substitutedaralkyl group or forms a bond together with the adjacent group R⁶; R⁶represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acylor unsubstituted or substituted aralkyl or R⁶ forms a bond together withR⁵; R⁷ represents hydrogen or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl,acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R⁸ representshydrogen or unsubstituted or substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkylgroups; n is an integer ranging from 1-4; m is an integer 0 or 1 and L¹is a leaving group such as halogen atom, p-toluenesulfonate,methanesulfonate, trifluoromethanesulfonate and the like, preferably ahalogen atom and a process for its preparation and its use in thepreparation of β-aryl-α-substituted hydroxyalkanoic acids is provided.

The compound of formula (If) where m=0 and all other symbols are asdefined may be prepared by reacting a compound of formula (Ic)

where R⁵, R⁶, R⁷, R⁸, Ar are as defined earlier, with a compound offormula (Ii)

L¹—(CH₂)_(n)—L²   (Ii)

where L¹ and L² may be same or different and represent a leaving groupsuch as Cl, Br, I, methanesulfonate, trifluoromethanesulfonate,p-toluenesulfonate and the like or L² may also represent a hydroxy or aprotected hydroxy group which may be later converted to a leaving group;n represents an integer ranging from 1-4.

The reaction of compound of formula (Ic) with a compound of formula (Ii)to produce a compound of formula (If) may be carried out in the presenceof solvents such as THF, DMF, DMSO, DME and the like or mixturesthereof. The reaction may be carried out in an inert atmosphere, whichmay be maintained by using inert gases such as N₂, Ar or He. Thereaction may be effected in the presence of a base such as K₂CO₃, Na₂CO₃or NaH or mixtures thereof. Acetone may be used as solvent when Na₂CO₃or K₂CO₃ is used as a base. The reaction temperature may range from 20°C.-120° C., preferably at a temperature in the range of 30° C.-80° C.The duration of the reaction may range from 1 to 24 hours, preferablyfrom 2 to 12 hours.

Alternatively, intermediate of formula (If) may be prepared by reactinga compound of formula (Ij)

L¹—(CH₂)_(n)—(O)_(m)Ar—CHO   (Ij)

where where L¹ represent a leaving group such as Cl, Br, I,methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate and thelike and all other symbols are as defined earlier, with a compound offormula (IIIb)

where all symbols are as defined earlier, to yield a compound of formula(IIIf) which is further reduced to yield a compound of formula (If). Thecompound of formula (IIIf) represents a compound of formula (If) whereinR⁵ and R⁶ together represent a bond and all other symbols are as definedearlier.

The reaction of compound of formula (Ij) with (IIIb) may be carried outin the presence of a base such as alkali metal hydrides like NaH, KH ororganolithiums like CH₃Li, BuLi and the like or alkoxides such as NaOMe,NaOEt, K⁺BuO⁻ or mixtures thereof. The reaction may be carried out inpresence of solvents, such as THF, dioxane, DMF, DMSO, DME and the likeor mixtures thereof. HMPA may be used as cosolvent The reactiontemperature may range from −78° C. to 50° C., preferably at atemperature in the range of −10° C. to 30° C. The reduction of compoundof the formula (IIIf) may be carried out in the presence of gaseoushydrogen and a catalyst such as PD/C, Rh/C, Pt/C, and the like. Mixturesof catalysts may be used. The reaction may also be conducted in thepresence of solvents such as dioxane, acetic acid, ethyl acetate,ethanol and the like. The nature of the solvent is not critical. Apressure between atmospheric pressure and 80 psi may be employed. Higherpressures may be used to reduce the reaction time. The catalyst may bepreferably 5-10% Pd/C and the amount of catalyst used may range from1-100% w/w. The reaction may also be carried out by employing metalsolvent reduction such as magnesium in alcohol or sodium amalgam inalcohol.

In another embodiment of the present invention there is provided a novelintermediate of formula (Ig)

where R¹, R², R³, R⁴ may be same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycrbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;the ring A fused to the ring containing X and N represents a 5-6membered cyclic structure containing carbon atoms, which may optionallycontain one or more heteroatoms selected from oxygen, sulfur or nitrogenatoms, which may optionally be substituted; the ring A may be saturatedor contain one or more double bonds or may be aromatic; X represents aheteroatom selected from oxygen, sulfur or NR⁹ where R⁹ is hydrogen,alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl oraralkoxycarbonyl groups; Ar represents an unsubstituted or substituteddivalent single or fused aromatic or heterocyclic group; R⁵ representshydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or unsubstituted orsubstituted aralkyl group or forms a bond together with the adjacentgroup R⁶; R⁶ represents hydrogen, hydroxy, alkoxy, halogen, lower alkylgroup, acyl or unsubstituted or substituted aralkyl or R⁶ forms a bondtogether with R⁵; R⁷ represents hydrogen or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl,acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; n is an integerranging from 1-4 and m is an integer 0 or 1, a process for itspreparation and its use in the preparation of β-aryl-α-substitutedhydroxyalkanoic acids.

The compound of formula (Ig) where R⁵ and R⁶ each represent hydrogenatoms and all other symbols are as defined earlier is prepared by aprocess outlined in Scheme-III.

The reaction of a compound of formula (IIIa) where all symbols are asdefined earlier with a compound of formula (Ik) where R⁷ is as definedearlier excluding hydrogen and Hal represent a halogen atom such as Cl,Br or I to produce a compound of formula (Il) may be carried out underconventional conditions in the presence of a base. The base is notcritical. Any base normally employed for Wittig reaction may beemployed, metal hydride such as NaH or KH; metal alkoxides such asNaOMe, K⁺BuO⁻ or NaOEt; metal amides such as LiNH₂ or LiN(iPr)₂. Aproticsolvent such as THF, DMSO, dioxane, DME and the like may be used.Mixture of solvents may be used. HMPA may be used as cosolvent. Inertatmosphere may be employed such as argon and the reaction is moreeffective under anhydrous conditions. Temperature in the range of −80°C. to 100° C. may be used.

The compound of (Il) where all symbols are as defined earlier and R⁷ isas defined earlier excluding hydrogen may be converted to a compound offormula (Im) where R⁵ and R⁶ represent hydrogen atoms and all othersymbols are as defined earlier, by treating with an alcohol of formulaR⁷OH where R⁷ represents unsubstituted or substituted groups selectedfrom alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,heterocyclyl, heteroaryl or heteroaralkyl under anhydrous conditions inthe presence of a strong anhydrous acid such as p-toluenesulfonic acid.

The compound of formula (Im) defined above upon treatment withtrialkylsilyl cyanide such as trimethylsilyl cyanide produces a compoundof formula (Ig) where R⁵ and R⁶ represent hydrogen atoms, R⁷ is asdefined earlier excluding hydrogen and all other symbols are as definedearlier.

In still another embodiment of the present invention the novelintermediate of formula (Ih)

where R¹, R², R³, R⁴ may be same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;the ring A fused to the ring containing X and N represents a 5-6membered cyclic structure containing carbon atoms, which may optionallycontain one or more heteroatoms selected from oxygen, sulfur or nitrogenatoms, which may optionally be substituted; the ring A may be saturatedor contain one or more double bonds or may be aromatic; X represents aheteroatom selected from oxygen, sulfur or NR⁹ where R⁹ is hydrogen,alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl oraralkoxycarbonyl groups; Ar represents an unsubstituted or substituteddivalent single or fused aromatic or heterocyclic group; R⁵ representshydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or unsubstituted orsubstituted aralkyl group or forms a bond together with the adjacentgroup R⁶; R⁶ represents hydrogen, hydroxy, alkoxy, halogen, lower alkylgroup, acyl or unsubstituted or substituted aralkyl or R⁶ forms a bondtogether with R⁵; R⁸ represents hydrogen or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl or heteroaralkyl groups; n is an integer ranging from 1-4 andm is an integer 0 or 1 and a process for its preparation and its use inthe preparation of β-aryl-α-substituted hydroxyalkanoic acids isprovided.

The compound of formula (Ih) where all other symbols are as definedearlier may be prepared by reacting a compound of formula (In)

where R⁶ is hydrogen atom and all other symbols are as defined earlier,with an appropriate diazotizing agent.

The diazotization reaction may be under conventional conditions. Asuitable diazotizing agent is an alkyl nitrile, such as iso-amylnitrile. The reaction may be carried out in presence of solvents such asTHF, dioxane, ether, benzene and the like or a combination thereof.Temperature in the range of −50° C. to 80° C. may be used. The reactionmay be carried out in an inert atmosphere which may be maintained byusing inert gases such as N₂, Ar or He. The duration of the reaction mayrange from 1 to 24 h, preferably, 1 to 12 h.

The compound of formula (In) may be prepared by a reaction between(IIIe) where all symbols are as defined earlier and a compound offormula (Io)

where R⁶ is hydrogen atom and all other symbols are as defined earlier.

The reaction of compound of formula (IIIe) where all symbols are asdefined earlier and a compound of formula (Io) where all symbols are asdefined earlier may be carried out in the presence of solvents such asTHF, DMF, DMSO, DME and the like or mixtures thereof. The reaction maybe carried out in an inert atmosphere which is maintained by using inertgases such as N₂, Ar or He. The reaction may be effected in the presenceof a base such as K₂CO₃, Na₂CO₃ or NaH or mixtures thereof. Acetone maybe used as a solvent when K₂CO₃ or Na₂CO₃ is used as a base. Thereaction temperature may range from 20° C.-120° C., preferably at atemperature in the range of 30° C.-80° C. The duration of the reactionmay range from 1 to 24 hours, preferably from 2 to 12 hours.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula (I) with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium t-butoxide,calcium hydroxide, magnesium hydroxide and the like, in solvents likeether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc.Mixture of solvents may be used. Organic bases such as diethanolamine,choline and the like; chiral bases like alkyl phenyl amine, phenylglycinol and the like; natural aminoacids such as lysine arginine,guanidine, and the like, unnatural aminoacids such as D-isomers orsubstituted aminoacids; ammonium or substituted ammonium salts andaluminum salts may also be used. Alternatively, acid addition saltswherever applicable are prepared by treatment with acids such ashdyrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, aceticacid, citric acid, maleic acid salicyclic acid, hydroxynaphthoic acid,ascorbic acid, palmitic acid, succinic acid, benzoic acid,benzenesulfonic acid, tartaric acid and the like in solvents like ethylacetate, ether, alcohols, acetone, THF, dioxate etc. Mixtures ofsolvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula (I) where YR⁹represents OH may be converted to a 1:1 mixture of diastereomeric amidesby treating with chiral amines, aminoacids, aminoalcohols derived fromaminoacids; conventional reaction conditions may be employed to convertacid into an amide, the diastereomers may be separated either byfractional crystallization or chromatography and the stereoisomers ofcompound of formula (I) may be prepared by hydrolyzing the purediastereomeric amide.

Various polymorphs of compound of general formula (I) forming part ofthis invention may be prepared by crystallization of compound of formula(I) under different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe nmr spectroscopy, ir spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

The present invention provides a pharmaceutical composition, containingthe compounds of the general formula (I) as defined above, theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their pharmaceutically acceptable salts or theirpharmaceutically acceptable solvates in combination with the usualpharmaceutically employed carriers, diluents and the like, useful forthe treatment and/or prophylaxis of diseases such as hypertension,coronary heat disease, atherosclerosid, stroke, peripheral vasculardiseases and related disorders. These compounds are useful for thetreatment of familial hypercholesterolemia, hypertriglyceridemia,lowering of atherogenic lipoproteins, VLDL and LDL. The compounds of thepresent invention can e used for the treatment of certain renal diseasesincluding glomerulonephritis, glomerulosclerosis, nephrotic syndrome,hypertensive nephrosclerosis, retinopathy, nephropathy. The compounds ofgeneral formula (I) are also useful for the treatment/prophylaxis ofinsulin resistance (type II diabetes), leptin resistance, impairedglucose tolerance, dyslipidemia, disorders related to syndrome X such ashypertension, obesity, insulin resistance, coronary heart disease, andother cardiovascular disorders. These compounds may also be useful asaldose reductase inhibitors, for improving cognitivie functions indementia, as inflammatory agents, treating diabetic complications,disorders related to endothelial cell activation, psoriasis, polycysticovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis,myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and for thetreatment of cancer. The compounds of the present inventions are usefulin the treatment and/or prophylaxis of the above said diseases incombination/concomittant with one or more HMG CoA reductase inhibitors,hypolipidemic/hypolipoproteinemic agents such as fibric acidderivatives, nicotinic acid, cholestyramine, colestipol, probucol ortheir combination. The compounds of the present invention in combinationwith HMG CoA reductase inhibitors, hypolipidemic/hypolipoproteinemicagents can be administered together or within such a period to actsynergistically. The HMG CoA reducts inhibitors may be selected fromthose used for the treatment or prevention of hyperlipidemia such aslovastatin, provastatin, simvastatin, flavastatin, atorvastatin,cerivastatin and their analogs thereof. Suitable fibric acid derivativemay be gemfibrozil, clofibrate, fenofibrate, ciprofibrate, benzafibrateand their analog thereof.

The present invention also provides a pharmaceutical composition,containing the compounds of the general formula (I) as defined above,their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptable saltsor their pharmaceutically acceptable solvates and one or more HMG CoAreductase inhibitors, hypolipidemic/hypolipoproteinemic agents such asfibric acid derivatives, nicotinic acid, cholestyramine, colestipol,probucol in combination with the usual pharmaceutically employedcarriers, diluents and the like.

The pharmaceutical composition may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like, may contain falvourants, sweeteners etc. in suitable solid orliquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. Such compositions typically containfrom 1 to 20%, preferably 1 to 10% by weight of active compound, theremainder of the composition being pharmaceutically acceptable carriers,diluents or solvents.

Suitable pharmaceutically acceptable carriers include solid fillers ordiluents and sterile aqueous or organic solutions. The active compoundwill be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the compounds can be combined witha suitable solid or liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions and the like. The pharmaceuticalcompositions, may, if desired, contain additional components such asflavourants, sweeteners, excipients and the like. For parenteraladministration, the compounds can be combined with sterile aqueous ororganic media to form injectable solutions or suspensions. For example,solutions in sesame or peanut oil, aqueous propylene glycol and the likecan be used, as well as solutions of water-solublepharmaceutically-acceptable acid addition salts or salts with base ofthe compounds. The injectable solutions prepared in this manner can thenbe administered intravenously, intraperiotoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

The compound of the formula (I) as defined above are clinicallyadministered to mammals, including man, via either oral or parenteralroutes. Administration by the oral route is preferred, being moreconvenient and avoiding the possible pain and irritation of injection.However, in circumstances where the patient cannot swallow themedication, or absorption following oral administration is impaired, asby disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.01 to about 100 mg/kg body weight of the subject per day orpreferably about 0.01 to about 30 mg/kg body weight per day administeredsingly or as a divided dose. However, the optimum dosage for theindividual subject being treated will be determined by the personresponsible for treatment, generally smaller doses being administeredinitially and thereafter increments made to determine the most suitabledosage.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

PREPARATION 1 Ethyl (E/Z)-3-[4-benzyloxyphenyl]-2-ethoxypropenoate

A solution of triethyl-2-ethoxyphosphonoacetate prepared by the methodof Grell and Machleidt, Annalen. Chemie, 1996, 699, 53 (3.53 g, 13.2mmol) in dry tetrahydrofuran (10 mL) was added slowly to a stirred icecooled suspension of sodium hydride (60% dispersion of oil) (0.62 g,25.94 mmol) in dry tetrahydrofuran (5 mL), under a nitrogen atmosphere.The mixture was stirred at 0° C. for 30 min. prior to the addition of a4-benzyloxybenzaldehyde (2.5 g, 11.79 mmol) in dry tetrahydrofuran (20mL). The mixture was allowed to warm up to room temperature and stirredat that temperature for further 20 h. The solvent was evaporated, water(100 mL) was added and extracted with ethyl acetate (2×75 mL). Thecombined organic extracts were washed with water (50 mL), brine (50 mL),dried (Na₂SO₄), filtered and the solvent was evaporated under reducedpressure. The residue was chromatographed over silica gel using amixture of ethyl acetate and pet. ether (2:8) as an eluent to afford thetitle compound (3.84 g, quantitative) as an oil. ¹H NMR of the productsuggests a (76:24=Z/E) mixture of geometric isomers (R. A. Aitken and G.L. Thom, Synthesis, 1989, 958).

¹H NMR (CDCl₃, 200 MHz): δ 1.25-1.50 (complex, 6H), 3.85-4.03 (complex,2H), 4.28 (q, J=7.0 Hz, 2H), 5.05, 5.09 (2s, 2H, benzyloxy CH₂), 6.08(s, 0.24H, E isomer of olefinic proton), 6.85-6.90 (complex, 2H), 6.99(s, 0.76H, Z isomer) 7.33-7.45 (complex, 5H), 7.75 (d, J=8.72 Hz, 2H).

PREPARATION 2 Methyl 3-[4-benzyloxyphenyl]-2-ethylpropanoate

A mixture of ethyl (E/Z)-3-[4-benzyloxyphenyl]-2-ethoxypropanoate (3.84g, 11.79 mmol obtained in the preparation 1) and magnesium turnings(5.09 g, 0.21 mol) in dry methanol (40 mL) was stirred at 25° C. for 1h. Water (80 mL) was added and pH of solution was adjusted to 6.5-7.5with 2N hydrochloric acid. The solution was extracted with ethyl acetate(3×75 mL). The organic layers were washed with water (50 mL), brine (50mL) dried (Na₂SO₄) and filtered. The solvent was evaporated underreduced pressure to afford the title compound (3.7 g, quantitativelyyield) as an oil.

¹H NMR (CDCl₃, 200 MHz): δ 1.16 (t, J=6.97 Hz, 3H), 2.95 (d, J=6.55 Hz,2H), 3.30-3.38 (complex, 1H), 3.55-3.67 (complex, 1H), 3.69 (s, 3H),3.99 (t, J=6.64 Hz, 1H), 5.04 (s, 2H), 6.89 (d, J=8.63 Hz, 2H), 7.15 (d,J=8.62 Hz, 2H), 7.31-7.41 (complex, 5H).

PREPARATION 3 Methyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate

A suspension of methyl 3-[4-(benzyloxyphenyl)-2-ethoxypropanoate (3.7 g,11.78 mmol; preparation 2) and 10% Pd-C (0.37 g) in ethyl acetate (50mL) was stirred at 25° C. under 60 psi hydrogen pressure for 24 h. Thecatalyst was filtered and the solvent was evaporated under reducedpressure. The residue was chromatographed over silica gel using amixture of ethyl acetate and pet. ether (2:8) and an eluent to affordthe title compound (2.2 g, 84%) as an oil.

¹H NMR (CDCl₃, 200 MHz): δ 1.21 (t, J=6.97 Hz, 3H), 2.99 (d, J=6.37 Hz,2H), 3.32-3.49 (complex, 1H), 3.57-3.65 (complex, 1H), 3.76 (s, 3H),4.05 (t, J=6.64 Hz, 1H), 5.19-5.40 (bs, 1H, D₂O exchangeable), 6.80 (d,J=8.44 Hz, 2H), 7.14 (d, J=8.39 Hz, 2H).

PREPARATION 4 Ethyl 3-[4-hydroxyphenyl]-2-ethoxypropanoate

The title compound (1.73 g, 61%) was prepared as a colourless oil fromethyl (E/Z)-3-[4-benzyloxyphenyl]-2-ethoxypropenote (3.85 g, 11.80 mmol)obtained in preparation 1 by hydrogenation procedure described inpreparation 3.

¹H NMR (CDCl₃, 200 MHz): δ 1.12-1.29 (complex, 6H), 2.93 (d, J=6.55 Hz,2H), 3.28-3.45 (complex, 1H), 3.51-3.68 (complex, 1H), 3.98 (t, J=6.55Hz, 1H), 4.16 (q, J=7.15 Hz, 2H), 5.40 (s, 1H, D₂O exchangeable), 6.73(d, J=8.39 Hz, 2H), 7.08 (d, J=8.53 Hz, 2H).

PREPARATION 5 Ethyl 3-[4-benzyloxyphenyl]-2-butoxypropanoate

A solution of ethyl 3-[4-benzyloxyphenyl)-2-hydroxypropanoate (5.0 g,16.6 mmol) (prepared in a similar manner as described in Ref:WO95/18125) in dry dimethyl formamide (5 mL) was added to a suspensionof sodium hydride (0.1 g, 41.6 mmol) (60% dispersion in oil) in drydimethyl formamide (3 mL) at 0° C. and stirring was continued forfurther 1 h. To the above reaction mixture n-butyl bromide (3.4 g, 24.0mmol) was added at 0° C. and stirring was continued for 10 h at ca. 25°C. Water (30 mL) was added and extracted with ethyl acetate 2×50 mL).The combined ethyl acetate layer was washed with water (50 mL), brine(25 mL), dried (Na₂SO₄), filtered and the solvent was evaporated. Theresidue was chromatographed over silica gel using a mixture of ethylacetate and the pet. ether (1:9) as an eluent to afford the titlecompound (0.7 g, 20%) as an oil.

¹H NMR (CDCl₃, 200 MHz): δ 0.85 (t, J=7.38 Hz, 3H), 1.18-1.40 (complex,5H), 1.49-1.58 (complex, 2H), 2.94 (d, J=6.74 Hz, 2H), 3.20-3.33(complex, 1H), 3.46-3.61 (complex, 1H), 3.94 (t, J=6.37 Hz, 1H), 4.16(q, J=7.0 Hz, 2H), 5.04 (s, 2H), 6.89 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.48Hz, 2H), 7.30-7.44 (complex, 5H).

PREPARATION 6 Ethyl 3-[4-hydroxyphenyl]-2-butoxypropanoate

The title compound (0.475 g, 75%) was prepared as an oil from ethyl3-[4-benzyloxyphenyl)-2-butoxypropanoate (0.85 g, 2.38 mmol) obtained inpreparation 8 by an analogous procedure to that described in preparation3.

¹H NMR (CDCl₃, 200 MHz): δ 0.85 (t, J=7.24 Hz, 3H), 1.19-1.38 (complex,5H), 1.44-1.58 (complex, 2H), 2.94 (d, J=6.55 Hz, 2H), 3.21-3.32(complex, 1H), 3.49-3.62 (complex, 1H), 3.94 (t, J=6.88 Hz, 1H), 4.16(q, J=7.1 Hz, 2H), 4.99 (s, 1H, D₂O exchangeable), 6.73 (d, J=8.53 Hz,2H), 7.09 (d, J=8.44 Hz, 2H).

PREPARATION 7 Ethyl 3-[4-benzyloxyphenyl]-2-hexyloxypropanoate

The title compound (1.2 g, 22%) was prepared as an oil from ethyl3-(4-benzyloxyphenyl)-2-hydroxypropanoate (4.2 g, 14.0 mmol) and1-bromohexane (3.4 g, 21.0 mmol) by an analogous procedure to thatdescribed in preparation 5.

¹H NMR (CDCl₃, 200 MHz): δ 0.86 (t, J=5.9 Hz, 3H), 1.18-1.37 (complex,7H), 1.45-1.66 (complex, 4H), 2.94 (d, J=6.55 Hz, 2H), 3.22-3.33(complex, 1H), 3.52-3.64 (complex 1H), 3.94 (t, J=6.9 Hz, 1H), 4.16 (q,J=7.06 Hz, 2H), 5.03 (s, 2H), 6.89 (d, J=8.63 Hz, 2H), 7.15 (d, J=8.63Hz, 2H), 7.31-7.44 (complex, 5H).

PREPARATION 8 Ethyl 3-[4-hydroxyphenyl]-2-hexyloxypropanoate

The title compound (0.7 g, 76%) was prepared as an oil from ethyl3-[4-benzyloxyphenyl)-2-hexyloxypropanoate (1.2 g, 3.1 mmol) obtained inpreparation 7 by an analogous procedure to that described in preparation3.

¹H NMR (CDCl₃, 200 MHz): δ 0.85 (t, J=5.81 Hz, 3H), 1.19-1.39 (complex,7H), 1.48-1.68 (complex, 4H), 2.92 (d, J=6.74 Hz, 2H), 3.18-3.39(complex, 1H), 3.48-3.62 (complex, 1H), 3.93 (t, J=7.0 Hz, 1H), 4.16 (q,J=7.06 Hz, 2H), 4.85 (s, 1H, D₂O exchangeable), 6.73 (d, J=8.53 Hz, 2H),7.10 (d, J=8.31 Hz, 2H).

PREPARATION 9 Ethyl (E/Z)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropenoate

The title compound (4.0 g, 66%) was prepared as an oil in 45:55 ratio ofE:Z isomers (as measured by ¹H NMR) from 4-(2-bromoethoxy)benzaldehyde(4.0 g, 17.4 mmol) and triethyl-2-ethoxyphosphonoacetate (5.61 g, 20.89mmol) by an analogous procedure to that described in preparation 1.

¹H NMR (CDCl₃, 200 MHz): δ 1.17 and 1.42 (6H, E and Z triplets, isomeric—OCH₂CH₃ and OCH₂—CH₃), 3.62-3.72 (complex, 2H), 3.90-4.28 (complex,2H), 4.30-4.37 (complex, 4H, 6.09 (s, 0.45H, olefinic proton of Eisomers), 6.85 and 6.92 (2H, d and d, J=8.67 Hz and 8.7 Hz), 6.98 (s,0.55H, Z isomer of olefinic proton), 7.16 and 7.78 (d and d, combined2H, J=8.63 Hz and 8.72 Hz).

PREPARATION 10 Ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate

The title compound (4.0 g, 80%) was prepared as colorless oil from ethyl(E/Z)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropenoate (5.0 g, 14.5 mmol)obtained in preparation 9 using H₂/10% Pd-C (4 g) in dioxane as asolvent by an analogous procedure to that described in preparation 3.

¹H NMR (CDCl₃, 200 MHz): δ 1.12-1.30 (complex, 6H), 2.95 (d, J=6.64 Hz,2H), 3.25-3.45 (complex, 1H), 3.56-3.68 (complex, 3H), 3.96 (t, J=6.65Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 4.27 (t, J=6.3 Hz, 2H), 6.81 (d, J=8.67Hz, 2H), 7.16 (d, J=8.63 Hz, 2H).

EXAMPLE 1 Ethyl(E/Z)-3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate

The title compound was obtained as 1:1 E:Z isomers (1.46 g,quantitative) as a syrupy liquid from4-[2-(phenothiazin-10-yl)ethoxy]benzaldehyde (1.08 g, 3.11 mmol) andtriethyl-2-ethoxyphosphonoacetate (W. Grell & H. Machleidt, Annalenchemie, 1966, 699, 53) (1.0 g, 3.73 mmol) by an analogous procedure tothat described in preparation 1.

¹H NMR (CDCl₃, 200 MHz): δ 1.15-1.43 (complex, 6H), 3.89-4.03 (complex,2H), 4.11-4.17 (complex, 2H), 4.30, 4.33 (complex, 4H,—CH₂CH₂-singlets), 6.07 (s, 0.5H, olefinic proton of E isomer),6.80-7.10 (complex, 6.5H), 7.14-7.20 (complex, 4H), 7.73 (d, J=8.39 Hz,2H).

EXAMPLE 2 Ethyl(E/Z)-3-[2-phenotiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate

The title compound was obtained as E:Z isomers (38:62) (as measured by¹H NMR) (1.5 g, 100%) as a colourless liquid from5-formyl-2-(phenothiazin-10-yl) methylbenzofuran (1.14 g, 3.2 mmol) by aprocedure similar to that described for preparation 1.

¹H NMR (CDCl₃, 200 MHz): δ 1.23-1.45 (complex, 6H), 3.55-3.78 (complex,1H), 3.88-4.19 (complex, 1H), 4.22-4.35 (complex, 2H), 5.14 (s, 2H),6.18 (s, 0.38H, olefinic proton of E isomer) 6.47 and 6.54(combined,1H), 6.78-7.12 (complex, 8.62H), 7.37-7.48 (complex, 1H), 7.71(d, J=7.57 Hz, 1H), 7.95 (s, 1H).

EXAMPLE 3 Ethyl(E/Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate

The title compound (14.4 g, 76%) was obtained as E:Z isomer (36:64) (asmeasured by ¹H NMR) as a white solid from4-[2-(phenoxazin-10-yl)ethoxy]benzaldehyde (14.0 g, 42.3 mmol) by ananalogous procedure to that described for preparation 1, mp: 110-112° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.16 and 1.38 (combined, 6H, isomeric—OCH₂CH₃ triplet signals), 3.89-4.05 (complex, 4H), 4.14-4.31 (complex,4H), 6.06 (s, 0.36H, olefinic proton of E isomer), 6.66-6.95 (complex,10.64H), 7.75 (d, J=8.76 Hz, 2H).

EXAMPLE 4 (±) Methyl3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate

The title compound (1.3 g, 94%) was prepared as a gummy liquid fromethyl(E/Z)-3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate(1.43 g, 3.10 mmol) obtained in example 1 by an analogous procedure tothat described in preparation 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.15 (t, J=7.00 Hz, 3H), 2.93 (d, J=6.64 Hz,2H), 3.33-3.42 (complex, 1H), 3.52-3.63 (complex, 1H), 3.69 (s, 3H),3.97 (t, J=6.20 Hz, 1H), 4.29 (s, 4H), 6.81 (d, J=8.62 Hz, 2H),6.92-6.96 (complex, 4H), 7.12-7.22 (complex, 6H).

EXAMPLE 5 (±) Methyl3-[2-(phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate

The title compound (1.0 g, 68%) was prepared as a gum, from ethyl(E/Z)-3-[2-(phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate(1.5 g, 3.0 mmol) obtained in example 2 by an analogous procedure tothat described in preparation 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.16 (t, J=7.00 Hz, 3H), 3.07 (d, J=6.55 Hz,2H), 3.30-3.49 (complex, 1H), 3.56-3.68 (complex, 1H), 3.70 (s,3H), 4.05(t, J=6.3 Hz, 1H), 5.13 (s, 2H), 6.48 (s, 1H), 6.79-7.48 (complex, 11H).

EXAMPLE 6 (±) Methyl3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate

Method A

The title compound (0.68 g, 52%) was prepared as a white solid, fromethyl (E/Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate(1.3 g, 2.9 mmol) obtained in example 3 by a procedure similar to thatdescribed in preparation 2, mp: 88-90° C.

Method B

A mixture of 2-(phenoxazin-10-yl)ethyl methanesulfonate (1.75 g, 5.0mmol), methyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (1.5 g, 0.68 mmol)obtained in preparation 3 and potassium carbonate (3.16 g) in drydimethylformamide (20 mL) was stirred for 12 h at 80° C. The reactionmixture was cooled to room temperature (ca. 25° C.). Water (30 mL) wasadded and extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with water (50 mL), dried (Na₂SO₄) and evaporated.The residue was chromatographed using a mixture of ethyl acetate andpet. ether (1:9) to afford the title compound (1.15 g, 47%) as a whitesolid, mp: 89-90° C. ¹H NMR data matches with the desired product (seeabove).

¹H NMR (CDCl₃, 200 MHz): δ 1.16 (t, J=6.92 Hz, 3H), 2.96 (d, J=6.64 Hz,2H), 3.22-3.40 (complex, 1H), 3.51-3.66 (complex, 1H), 3.68 (s, 3H),4.00 (t, J=7.0 Hz, 1H), 4.18 (complex, 4H), 6.55-6.89 (complex, 10H),7.12 (d, J=8.63 Hz, 2H).

EXAMPLE 7 (±) Ethyl3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate

Method A

To a solution ethyl(E/Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate (1.0g, 2.24 mmol) obtained in example 3 in dioxane (50 mL) was added 10%Pd-C (0.25 g) and stirred at 25° C. under 60 psi hydrogen pressure for24 h. At the end of this time reaction mixture was filtered and thesolvent was evaporated under reduced pressure. The residue wastriturated with pet. ether to afford the title compound (0.96 g, 96%) asa white solid, mp: 51-53° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.12-1.27 (complex, 6H), 2.94 (d, J=6.31 Hz,2H), 3.26-3.41 (complex, 1H), 3.52-3.75 (complex, 1H), 3.96 (t, J=6.64Hz, 2H), 4.10-4.28 (complex, 5H), 6.55-6.92 (complex, 10H), 7.16 (d,J=8.39 Hz, 2H).

Method B

The title compound (0.55 g, 75%) was prepared as a white solid from2-(phenoxazin-10-yl)ethyl methanesulfonate (0.5 g, 1.63 mmol) and ethyl3-(4-hydroxyphenyl)-2-ethoxypropanoate (0.46 g, 1.9 mmol) obtained inpreparation 4 by a procedure similar to that described in example 6(Method B). mp: 52-53° C. The ¹H NMR data matches with the desiredproduct (see above).

Method C

To a suspension of sodium hydride (60% dispersion in oil) (0.098 g, 4.0mmol) in dry dimethyl formamide (3 mL) was added a solution ofphenoxazine (0.3 g, 1.6 mmol) in dry dimethyl formamide (5 mL) at 0° C.under nitrogen atmosphere and stirred for 30 min at ca. 25° C. To theabove reaction mixture a solution of ethyl3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate (0.85 g, 2.4 mmol)obtained in preparation 10 in dry dimethyl formamide (5 mL) at 0° C. andstirring was continued for a further 10 h at ca. 25° C. Water (40 mL)was added and extracted with ethyl acetate (2×30 mL). The combinedorganic extracts were washed with water (25 mL), brine (25 mL), dried(Na₂SO₄), filtered and evaporated. The residue was chromatographed oversilica gel using a mixture of ethyl acetate and pet. ether (1:9) as aneluent to afford the title compound (0.3 g, 40%) as a colourless solid.mp: 52-53° C. The ¹H NMR data matches with the desired product (seeabove).

EXAMPLE 8 (±) Ethyl3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate

The title compound (1.06 g, 43%) was prepared as a pale yellow liquidfrom (2-phenoxazin-10-yl)ethyl methanesulfonate (1.8 g, 5.9 mmol) andethyl 3-(4-hydroxyphenyl)-2-hydroxy propanoate (1.36 g, 6.49 mmol) by ananalogous procedure to that described in example 6 (Method B).

¹H NMR (CDCl₃, 200 MHz): δ 1.29 (t, J=6.96 Hz, 3H), 2.85-3.12 (complex,2H), 3.92 (bs, 2H), 4.10-4.27 (complex, 4H), 4.39 (t, J=6.1 Hz, 1H),6.68-6.89 (complex, 10 H), 7.13 (d, J=8.39 Hz, 2H). OH proton is toobroad to observe.

EXAMPLE 9 (±) Ethyl3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoate

The title compound (0.25 g, 53%) was prepared as a colourless liquidfrom 2-(phenoxazin-10-yl)ethyl methanesulfonate (0.3 g, 0.98 mmol) andethyl 3-(4-hydroxyphenyl)-2-butoxy propanoate (0.26 g, 0.97 mmol)obtained in preparation 6 by an analogous procedure to that described inexample 6 (Method B).

¹H NMR (CDCl₃, 200 MHz): δ 0.92 (t, J=6.40 Hz, 3H), 1.21-1.39 (complex,5H), 1.45-1.58 (complex, 2H), 2.94 (d, J=6.32 Hz, 2H), 3.24-3.31(complex, 1H), 3.50-3.57 (complex, 1H), 3.94 (t, J=6.13 Hz, 1H),4.13-4.23 (complex, 6H), 6.61-6.84 (complex, 10 H), 7.16 (d, J=8.3 Hz,2H).

EXAMPLE 10 (±) Ethyl3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoate

The title compound (0.52 g, 53%) was prepared as a pale yellow oil from2-(phenoxazin-10-yl)ethyl methanesulfonate (0.6 g and 1.97 mmol) andethyl 3-(4-hydroxyphenyl)-2-hexyloxypropanoate (0.70 g, 2.4 mmol)obtained in preparation 8 by an analogous procedure to that described inexample 6 (Method B).

¹H NMR (CDCl₃, 200 MHz): δ 0.85 (t, J=6.00 Hz, 3H), 1.20-1.27 (complex,7H), 1.48-1.57 (complex, 4H), 2.94 (d, J=6.00 Hz, 2H), 3.21-3.30(complex, 1H), 3.52-3.56 (complex, 1H), 3.90-3.99 (complex, 3H),4.13-4.22 (complex, 4H), 6.60-6.83 (complex, 10 H), 7.15 (d, J=8.62 Hz,2H).

EXAMPLE 11 (±)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid

To a solution of (±) methyl3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate (7.5 g,16.70 mmol) obtained in example 4 in methanol (50 mL) was added aqueous10% sodium hydroxide (20 mL). The reaction mixture was stirred at ca.25° C. for 3 h. The solvent was removed under reduced pressure and theresidue was acidified with 2 N hydrochloric acid, extracted with ethylacetate (2×100 mL). The combined ethyl acetate extract was washed withwater (50 mL), brine (50 mL), dried (Na₂SO₄), filtered and solvent wasevaporated under reduced pressure. The residue was chromatographed oversilica gel using a mixture of dichloromethane and methanol (9:1) as aneluent to afford the title compound (6.0 g, 83%) as a white solid. mp:79-82° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.18 (t, J=6.80 Hz, 3H), 2.88-3.11 (complex,2H), 3.39-3.64 (complex, 2H), 4.06 (dd, J=9.2 and 4.3 Hz, 1H), 4.30 (s,4H), 5.30-5.98 (bs, 1H, D₂O exchangeable), 6.80-7.02 (complex, 6H),7.12-7.21 (complex, 6H).

EXAMPLE 12 (±)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,sodium salt

A mixture of (±)3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3g, 0.689 mmol) obtained in example 11 and sodium methoxide (0.041 g,0.758 mmol) in methanol (5 mL) was stirred at ca. 25° C. for 2 h. Thesolvent was removed under reduced pressure and the residue wastriturated with dry ether (3×10 mL). The separated solid was filtered,washed with dry ether (2×5 mL) and dried over P₂O₅ under reducedpressure to afford the title compound (0.25 g, 89%) as a white solid.mp: 188-191° C.

1H NMR (DMSO-d₆, 200 MHz): δ 1.04 (t, J=6.90 Hz, 3H), 2.71-2.89(complex, 1H), 2.90-3.06 (complex, 1H), 3.16-3.30 (complex, 1H),3.36-3.54 (complex, 1H), 3.88-3.91 (complex, 1H), 4.21 (s, 4H), 6.72 (d,J=8.3 Hz, 2H), 6.89-6.99 (complex, 4H), 7.05-7.21 (complex, 6H).

EXAMPLE 13 (±)3-[2-(Phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic acid

The title compound (0.8 g, 83%) was prepared as a white solid from (±)methyl3-[2-(phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate (1.0g, 2.0 mmol) obtained in example 5 by a procedure analogous to thatdescribed in example 11. mp: 120-121° C. COOH proton is too broad toobserve.

¹H NMR (CDCl₃, 200 MHz): δ 1.15 (t, J=6.95 Hz, 3H), 3.00-3.26 (complex,2H), 3.40-3.68 (complex, 2H), 4.08 (t, J=4.47 Hz, 1H), 5.11 (s, 2H),6.46 (s, 1H), 6.77-7.40 (complex, 11H).

EXAMPLE 14 (±)3-[2-(Phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic acid,sodium salt

The title compound (0.12 g, 67%) was prepared as a white solid from (±)3-[2-(phenothiazin-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic acid(0.16 g, 0.38 mmol) obtained in example 13 by a procedure analogous tothat described for example 12. mp: 258-261° C.

¹H NMR (CDCl₃, 200 MHz): δ 0.95 (t, J=6.97 Hz, 3H), 2.62-2.80 (complex,1H), 2.89-3.02 (complex, 1H), 3.06-3.18 (complex, 1H), 3.22-3.31(complex, 1H), 3.50-3.61 (complex, 1H), 5.25 (s, 2H), 6.64 (s, 1H),6.90-7.39 (complex, 1H).

EXAMPLE 15 (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid

The title compound (5.4 g, 77%) was prepared as a white solid from (±)methyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate (7.5g, 16.8 mmol) obtained in example 6 by a procedure similar to thatdescribed in example 11. mp: 90-92° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.19 (t, J=7.00 Hz, 3H), 2.90-3.18 (complex,2H), 3.41-3.62 (complex, 2H), 3.90-4.10 (complex, 3H), 4.18 (t, J=6.20Hz, 2H), 6.58-6.89 (complex, 10H), 7.16 (d, J=8.40 Hz, 2H). COOH protonis too broad to observe.

EXAMPLE 16 (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, sodiumsalt

The title compound (0.27 g, 85%) was prepared as a white solid from (±)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g,0.72 mmol) obtained in example 15 by an analogous procedure to thatdescribed in example 12. mp: 194-202° C.

¹H NMR (CDCl₃, 200 Mhz): δ 0.92 (t, J=6.97 Hz, 3H), 2.65-2.82 (complex,1H), 2.96-3.14 (complex, 2H), 3.31-3.41 (complex, 1H), 3.70-3.90(complex, 3H) 3.94-4.04 (complex, 2H), 6.47-6.74 (complex, 10 H), 7.05(d, J=8.30 Hz, 2H).

EXAMPLE 17 (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid

The title compound (0.40 g, 72%) was prepared as a brown liquid from (±)ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.6g, 1.43 mmol) obtained in example 8 by an analogous procedure to thatdescribed in example 11.

¹H NMR (CDCl₃, 200 MHz) δ: 2.75 (bs, 1H, D₂O exchangeable), 2.86-3.23(complex, 2H), 3.85 (t, J=6.0 Hz, 2H), 4.18 (t, J=5.90 Hz, 2H), 4.47(complex, 1H), 6.58-6.89 (complex, 10H), 7.17 (d, J=8.63 Hz, 2H). COOHproton is too broad to observe.

EXAMPLE 18 (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoic acid

The title compound (0.13 g, 69%) was prepared as a cream coloured solidfrom (±) ethyl3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoate (0.2 g, 0.42mmol) obtained in example 9 by an analogous procedure to that describedin example 11. mp: 84-88° C.

¹H NMR (CDCl₃, 200 MHz): δ 0.88 (t, J=7.50 Hz, 3H), 1.26-1.47 (complex,2H), 1.47-1.66 (complex, 2H), 2.87-3.16 (complex, 2H), 3.35-3.58(complex, 2H), 3.88-4.08 (complex, 3H), 4.15 (t, J=6.4 Hz, 2H),6.65-6.86 (complex, 10H), 7.15 (d, J=8.63 Hz, 2H), COOH proton is toobroad to observe.

EXAMPLE 19 (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoic acid, sodiumsalt

The title compound (0.07 g, 83%) was prepared as a cream colouredhygroscopic solid from (±)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoic acid (0.08 g,0.178 mmol) obtained in example 18 by a procedure similar to thatdescribed in example 12.

¹H NMR (DMSO-d₆, 200 MHz), δ 0.78 (t, J=7.28 Hz, 3H),1.19-1.523(complex, 4H), 2.72-3.02 (complex, 2H), 3.45-3.67 (complex,2H), 4.01 (bs, 3H), 4.18 (bs, 2H), 6.61-6.89 (complex, 8H), 7.10-7.24(complex, 4H).

EXAMPLE 20 (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoic acid

The title compound (0.10 g, 23%) was obtained as a syrupy liquid from(±) ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoate(0.46 g, 0.86 mmol) obtained in example 10 by an analogous procedure tothat described in example 11.

¹H NMR (CDCl₃, 200 MHz): δ 0.86 (t, J=6.00 Hz, 3H), 1.18-1.30 (complex,4H), 1.42-1.80 (complex, 4H), 2.88-3.18 (complex, 2H), 3.32-3.60(complex, 2H), 3.89-4.09 (complex, 3H), 4.16 (t, J=6.0 Hz, 2H),6.58-6.89 (complex, 10H), 7.14 (d, J=8.63 Hz, 2H). COOH is too broad toobserve.

EXAMPLE 21[(2R)-N(1S)]-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide(21a)

[(2S)-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide(21b)

To an ice cooled solution of(±)-3-[4-[2-(phenoxazin-10-yl)-ethoxy]phenyl]-2-ethoxypropanoic acid(1.2 g, 2.9 mmol) obtained in example 15 and triethylamine (0.48 g, 5.8mmol) in dry dichloromethane (25 mL) was added pivaloyl chloride (0.38g, 3.19 mmol) and stirred for 30 min at 0° C. A mixture of(S)-2-phenylglycinol (0.39 g, 2.9 mmol) and triethylamine (0.58 g, 5.8mmol) in dichloromethane (20 mL) was added to the above reaction mixtureat 0° C. and stirring was continued for further 2 h at 25° C. Water (50mL) was added and extracted with dichloromethane (2×50 mL). The organicextracts were washed with water (2×25 mL), brine (25 mL), dried (Na₂SO₄)and evaporated. The residue was chromatographed over silica gel using agradient of 40-60% ethyl acetate in pet. ether as an eluent to affordfirstly a diastereomer tentatively assigned as [2R,N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide(0.55 g, 35%) (21 a) followed by[2S-N(1S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.5 g, 32%) (21b).

21a: mp: 126-128° C.

[α]_(D) ²⁵=+24.6 (c=1.0%, CHCl₃).

¹H NMR (CDCl₃, 200 MHz): δ 1.16 (t, J=7.20 Hz, 3H), 2.50 (bs, 1H, D₂Oexchnageable), 2.92-3.20 (complex, 2H), 3.52 (q, J=7.05 Hz, 2H), 3.72(bs, 2H), 3.99 (complex, 3H), 4.21 (t, J=6.64 Hz, 2H), 4.98-5.01(complex, 1H), 6.64-6.70 (complex, 5H), 6.73-6.89 (complex, 4H), 7.03(d, J=7.15 Hz, 1H), 7.18-7.29 (complex, 4H), (J=7.32-7.39 complex, 3H).CONH is too broad to observe.

21b: mp: 139-141° C.

[α]_(D) ²⁵=−13.3 (c, 1.00% CHCl₃)

¹H NMR (CDCl₃, 200 MHz); δ 1.18 (t, J=6.96 Hz, 3H), 2.05 (bs, 1H, D2Oexchangeable), 2.80-3.14 (complex, 2H), 3.54 (q, J=7.00 Hz, 2H), 3.85(bs, 2H), 3.97 (complex, 3H), 4.41 (t, J=6.23 Hz, 2H), 4.92-5.01(complex, 1H), 6.62-6.85 (complex, 9H), 7.02-7.20 (complex, 5H),7.26-7.30 (complex, 3H), CONH is too broad to observe.

EXAMPLE 22 (+)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid:

A solution of [2R, diastereomer,N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide(0.45 g, 0.84 mmol) obtained in example 21a in mixture of 1M sulphuricacid (17 mL) and dioxane/water (1:1, 39 mL) was heated at 90° C. for 88h. The pH of the mixture was adjusted to 3.0 by addition of an aqueoussodium hydrogen carbonate solution. The mixture was extracted with ethylacetate (2×25 mL) and the organic extract was washed with water (50 mL),brine (25 mL), dried (Na₂SO₄) and evaporated. The residue waschromatographed over silica gel using a gradient of 50-75% ethyl acetatein pet, ether to afford the title compound (0.2 g, 57%) as a whitesolid. mp: 77-78° C.

[α]_(D) ²⁵=+12.1 (c=1.0%, CHCl₃)

¹H NMR (CDCl₃, 200 MHz): δ 1.16 (t, J=7.0 Hz, 3H), 1.43-1.85 (bs, 1H,D₂O exchangeable), 2.86-3.14 (complex, 2H), 3.40-3.67 (complex, 2H),3.90-4.08 (complex, 3H), 4.15 (t, J=6.65 Hz, 2H), 6.59-6.83 (complex, 10H), 7.13 (d, J=8.4 Hz, 2H).

EXAMPLE 23 (−)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid:

The title compound (0.19 g, 54%) was prepared as a white solid fromdiastereomer[(2S-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenyl)ethylpropanamide(0.45 g, 0.84 mmol) obtained in example 21b by an analogous procedure tothat described in example 22. mp: 89-90° C.

[α]_(D) ²⁵=−12.6 (c=1.0% CHCl₃)

¹H NMR (CDCl₃, 200 MHz): δ 1.16 (t, J=7.02 Hz, 3H), 1.42-1.91 (bs, 1H,D₂O exchangeable), 2.94-3.15 (complex, 2H), 3.40-3.65 (complex, 2H),3.86-4.06 (complex, 3H), 4.15 (t, J=6.65 Hz, 2H), 6.63-6.83 (complex,10H), 7.13 (d, J=8.54 Hz, 2H).

EXAMPLE 24 (±)3-[4-(2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,potassium salt:

A mixture of (±)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g,0.72 mmol) obtained in example 15 and potassium tert. butoxide (88 mg,0.72 mmol) in methanol (5 ml) was stirred at ca. 25° C. for 2h. Thesolvent was removed under reduced pressure and the residue wastriturated with dry ether (3×3 mL). The supernatant solvent was decantedand further traces of ether was removed and dried under reduced pressureto afford the title compound (0.25 g, 76%) as a hygroscopic solid.

¹H NMR (CDCl₃, 200 MHz): δ 0.96-1.03 (t, J=6.82 Hz, 3H), 2.55-2.65 (m,3H), 2.81-2.90 (m, 1H), 3.10-3.40 (t, J=7.05 Hz, 1H), 4.01-4.07 (t,J=5.30 Hz, 2H), 4.18-4.23 (t, J=5.30 Hz, 2H), 6.60-7.00 (m, 10 H), 7.1(d, J=8.30 Hz, 2H).

EXAMPLE 25 (−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,magnesium salt:

To a solution of (−)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g,0.72 mmol) obtained in example 23 in methanol (10 mL) was addedmagnesium hydroxide (20 mg, 0.345 mmol). The reaction mixture wasstirred at room temperature ca. 25° C. for 72 h. The solvent wasevaporated and the residue was triturated with diethyl ether anddecanted to yield the title compound as a white solid (280 mg, 90%). mp:300° C. (decomp).

[α]_(D) ²⁵=−31.0 (c=1.0%, CHCl3)

¹H NMR (CD₃OD, 200 MHz): δ 1.10 (t, J=7.00 Hz, 3H), 2.80 (dd, J=8.39Hz,14Hz, 1H), 3.0 (dd, J=3.83 Hz, 1H), 3,20-3.40 (m, 1H), 3.50-3.70 (m,1H), 3.80-3.90 (m, 1H), 3.99 (t, J=5.90 Hz, 2H), 4.20 (t, J=5.90 Hz,2H), 6.54-6.90 (m, 6H), 7.16 (d, J=8.50 Hz, 2H).

EXAMPLE 26 (±)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,arginine salt:

A mixture of (±)3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl-2-ethoxypropanoic acid (50 mg,0.115 mmol) obtained in example 11 and L-arginine (20 mg, 0.115 mmol) inmethanol (3.0 mL) was stirred for 14 h at 30° C. Methanol was removedunder reduced pressure and the residual mass was triturated with etherto afford the title compound as a white solid (62 mg, 88%). mp: 178° C.

¹H NMR (DMSO-d₆, 200 MHz): δ 1.08 (t, J=6.90 Hz, 3H), 1.72-1.84 (m, 4H),2.86-2.90 (m, 2H), 3.16-3.30 (m, 4H), 3.52-3.56 (m, 2H), 3.68-3.91 (m,2H), 4.28 (s, 4H), 6.70 (d, J=8.66 Hz, 2H), 6.74-6.96 (m, 2H), 7.00-7.23(m, 8H).

EXAMPLE 27 (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,arginine salt:

A solution of L-arginine (41.5 mg, 0.23 mmol) in water (0.25 mL) wasadded to a stirred solution of (+)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl-2-ethoxypropanoic acid (100 mg,0.23 mmol) obtained in example 22 in ethanol (1 mL) at room temperatureca. 25° C. The reaction mixture was stirred vigorously for 16 h at thesame temperature. The precipitated solid was filtered and dried underreduced pressure to yield the title compound (110 mg, 78%). mp: 196-198°C.

[α]_(D) ²⁵=+24.0 (c=0.5%, CHCl3)

¹H NMR (CD₃OD, 200 MHz): δ 1.04-1.11 (t, J=7.06 Hz, 3H), 1.71-1.87 (m,4H), 2.78-2.90 (m, 2H), 3.18-3.26 (m, 3H), 3.54-3.58 (m, 2H), 3.75-3.85(m, 1H), 3.96-4.01 (t, J=5.81 Hz, 2H, 4.17-4.23 (t, J=5.82 Hz, 2H),6.60-6.82 (m, 10H), 7.15-7.19 (d, J=8.40 Hz, 2H).

EXAMPLE 28 (−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,arginine salt:

A mixture of(−)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acidobtained in example 23 (104.3 mg, 0.24 mmol) and L-arginine (43.3 mg,0.25 mmol) in a mixture of ethanol (2.5 mL) and water (0.15 mL) wasstirred for 24h at room temperature. The white precipitate formed wasfiltered and the solid was washed with dry ether (10-15 mL) to yield thetitle compound as a white solid (100 mg, 67.7%). mp: 145-147° C.

[α]_(D) ²⁵=−24 (C=0.545%, MeOH)

¹H NMR (DMSO-D6): δ 1.10 (t, J=7.06 Hz, 3H), 1.72-1.86 (m, 4H),2.81-2.92 (m, 2H), 3.19-3.25 (m, 3H), 3.56-3.60 (m, 2H), 3.75-3.85 (m,1H), 3.97-4.03 (t, J=5.72 Hz, 2H), 4.19-4.25 (t, J=5.82 Hz, 2H),6.58-6.84 (m, 10H), 7.17-7.21 (d, J=8.27 Hz, 2H).

EXAMPLE 29 (−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, lysinesalt:

A mixture of (−)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (50 mg,0.119 mmol) obtained in example 23 and lysine (17.5 mg, 0.119 mmol) inmethanol (3.0 mL) was stirred for 36 h at room temperature ca. 25° C.under nitrogen atmosphere. Methanol was removed under reduced pressureand the residual mass was triturated with ether to afford the titlecompound as a white solid (65 mg, 96.4%), mp: 153-155° C.

[α]_(D) ²⁵=−14.0 (c=0.5% CHCl₃)

¹H NMR (CD₃OD, 200 MHz): δ 1.11 (t, J=7.01 Hz, 3H), 1.42-1.92 (m, 6H),2.79 (q, J=7.05 Hz, 2H), 2.95 (dd, J=4.00, 12.6 Hz, 1H), 3.15-3.45 (m,2H), 3.48-3.70 (m, 1H), 3.78 (dd, J=8.97, 4.00 Hz, 1H), 4.02 (t, J=5.80Hz, 2H), 4.23 (t, J=5.85 Hz, 2H), 6.59-6.90 (m, 10H), 7.22 (d, J=8.73Hz, 2H).

EXAMPLE 30 (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoicacid, sodium salt:

To a solution of (±)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-methyl-2-phenoxypropanoicacid (210 mg, 0.43 mmol) in dry methanol (4 mL) was added freshlyprepared sodium methoxide (23 mg, 0.42 mmol) and allowed to stir thereaction mixture at 30° C. for about 2 h. Methanol was removed underreduced pressure and the residue was triturated with dry ether (3×5 mL)to afford the title compound as white hygroscopic solid (200 mg, 91%).

¹H NMR (DMSO, 200 MHz): δ 1.1 (s, 3H), 3.00-3.10 (dd, J=13.7 Hz, 2H),3.90 (d, J=5.00 Hz, 2H), 4.18 (d, J=5.30 Hz, 2H), 6.60-6.90 (m, 8H),7.10-7.30 (m, 4H).

EXAMPLE 31 (−) 3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt:

A mixture of (−)3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (78mg, 0.23 mmol) and L-arginine (34 mg, 0.23 mmol) in methanol (3 mL) wasstirred for 14 h at 30° C. The solvent was removed and the residue wastriturated with either or yield the title compound as white solid (70mg, 64%), mp: 194° C.

¹H NMR (DMSO-D6): δ 1.08 (t, J=6.90 Hz, 3H), 3H), 1.73-1.84 (m, 4H),2.83-2.90 (m, 2H), 3.15-3.31 (m, 4H), 3.53-3.55 (m, 2H), 3.70-3.90 (m,2H), 4.28 (s, 4H), 6.79 (d, J=8,60 Hz, 2H), 6.76-6.98 (m, 2H), 7.01-7.21(m, 8H).

EXAMPLE 32 (−)3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,lysine salt:

A mixture of(−)-3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid(50 mg, 0.1079 mmol) and L-lysine (18 mg, 0.1079 mmol) in methanol (1mL) was stirred for 14 h at room temperature. The solvent was removedand the residue was treated with dry ether (5 mL×2). The gummy mass wasscratched when a pale solid separated from the ether layer. The etherlayer was decanted to yield the title compound (55 mg, 85%). mp:138-140° C.

[α]_(D) ²⁵=−1.28 (C=0.5%, MeOH)

¹H NMR (CDCl₃, 200 MHz): δ 1.07 (t, J=6.95 Hz, 3H), 1.51-1.89 (m, 4H),2.87-2.94 (m, 2H), 3.29-3.30 (m, 5H), 3.50-3.53 (m, 2H), 3.71-3.80 (m,1H), 4.28 (s, 4H), 6.76-6.80 (m, 2H), 6.92-6.95 (m, 2H), 7.01-7.21 (m,8H).

EXAMPLE 33 (±)3-[4-[2-Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid, sodiumsalt:

The title compound (80 mg, 47.33%) was prepared from (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid (160mg, 0.49 mmol) obtained in example 17 by an analogous procedure to thatdescribed in example 12. mp: >280° C.

¹-H NMR ((DMSO-D6, 200 MHz): δ 2.88-2.96 (m, 2H), 4.01-4.404 (d, J=5.31Hz, 2H), 4.15-4.18 (d, J=5.07 Hz, 2H), 6.60-6.90 (m, 10H), 7.10-7.20 (d,J=8.54 Hz, 2H).

EXAMPLE 34 (±) Methyl3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate:

A solution of ethyl diethylphosphino phenoxy acetate in dry THF wasadded slowly to a stirred ice cooled suspension of sodium hydride in dryTHF under nitrogen atmosphere. The mixture was stirred at 0° C. for 30min. and added a solution of 4-[2-(Phenoxazin-10-yl)ethoxy]benzaldehydein dry THF dropwise at ice temperature. The mixture was allowed to warmto room temperature and stirred for overnight. The solvent wasevaporated under reduced pressure, residue was diluted with water andextracted with ethylacetated. The organic layer was washed with water,brine, dried and concentrated. The residue was chromatographed with 10%ethylacetate in pet, ether as an eluent to afford ethyl3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate (59%) asthick liquid. Ethyl3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate (3.5 gm)and magnesium turnings in dry methanol was stirred at room temp for 12h. Methanol was evaporated and the residue was taken into water,acidified with 2N HCl and extracted with ethylacetate. The organic layerwas washed with water, brine, evaporated and chromatographed with 10%ethylacetate in per. ether to yield the title compound (2.9 g, 85%). mp:106-110° C.

¹H NMR ((CDCl₃, 200 MHz): δ 3.16-3.20 (d, J=6.23 Hz, 2H), 3.70 (s, 3H),4.16 (m, 4H), 4.72-4.79 (t, J=6.32 Hz, 1H), 6.63-7.27 (m, 17H).

EXAMPLE 35 (±)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acid:

To a solution of (±) methyl3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate (300 mg,0.6 mmol) obtained in example 34 in methanol (15 mL) was added 10% NaOHsolution (5 mL). The reaction was stirred at room temperature for 10 h.Methanol was removed and the residue was acidified with 2N HCl,extracted with ethylacetated (3×10 mL). The organic layer was washedwith water, brine, dried and concentrated. The residue waschromatographed using 30% ethylacetate:pet, ether to afford a thirdliquid which was triturated with per ether to yield the title compoundas a solid (192 mg, 66%). mp: 119-120° C.

¹H NMR (CDCl₃, 200 MHz): δ 3.23-3.26 (d, J=5.81 Hz, 2H), 3.94-4.00 (t,J=6.23 Hz, 2H), 4.14-4.20 (t, J=6.64 Hz, 2H), 4.81-4.87 (t, J=6.23 Hz,1H), 6.61-6.89 (m, 12H), 6.96-7.04 (t, J=7.31 Hz, 1), 7.21-7.32. (m,4H).

The compounds of the present invention lowered random blood sugar level,triglyceride, total cholesterol, LCL, VLDL and increased HDL. This wasdemonstrated by in vitro as well as in vivo animal experiments.

Demonstration of Efficacy of Compounds:

A) In vitro:

a) Determination of hPPARα activity:

Ligand binding domain of hPPARα was fused to DNA binding domain of Yeasttranscription factor GAL4 in eucaryotic expression vector. Usingsuperfect (Qiagen, Germany) as transfecting reagent HEK-293 cells weretransfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat different concentrations after 42 hrs of transfection and incubatedovernight. Luciferase activity as a function of compoundbinding/activation capacity of PPARα was measured using Packard Luclitekit (Parkard, USA) in Top Count (Ivan Sadowski, Brendan Bell, PeterBroag and Melvyn Hollis. Gene. 1992, 118:137-141; Superfect TransfectionReagent Handbook, February, 1997. Qiagen, Germany).

b) Determination of hPPARγ activity:

Ligand binding domain of hPPARγ1 was fused to DNA binding domain ofYeast transcription factor GAL4 in eucaryotic expression vector. Usinglipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293 cellswere transfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat 1 μM concentration after 48 hrs of transfection and incubatedovernight. Luciferase activity as a function of drug binding/activationcapacity of PPARγ1 was measured using Packard Luclite kit (Packard, USA)in Packard Top Count (Ivan Sadowksi, Brendan Bell, Peter Broag andMelvyn Hollis. Gene. 1992. 118:137-141; Guide to EukaryoticTransfections with Cationic Lipid Reagents. Life Technologies, GIBCOBRL, USA).

Example No Concentration PPARα Concentration PPARγ Example 11 50 μM 6.42Fold 1 μM 5.20 Fold Example 15 50 μM 3.30 Fold 1 μM  6.0 Fold Example 2850 μM  9.5 Fold 1 μM 12.8 Fold Example 29 50 μM  6.0 Fold 1 μM  5.0 FoldExample 30 50 μM  9.3 Fold 1 μM 13.9 Fold

c) Determination of HMG CoA reductase inhibition activity:

Liver microsome bound reductase was prepared from 2% cholestyramine fedrats at mid-dark cycle. Spectrophotometric assays were carried out in100 mM KH₂PO₄, 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 μg ofliver microsomal enzyme. Total reaction mixture volume was kept as 1 mL.Reaction was started by addition of HMB CoA. Reaction mixture wasincubated at 37° C. for 30 min and decrease in absorbance at 340 nm wasrecorded. Reaction mixture without substrate was used as blank(Goldstein, J. L. and Brown, M. S. Progress in understanding the LDLreceptor and HMG CoA reductase, two membrane proteins that regulate theplasma cholesterol, J. Lipid Res. 1984, 25: 1450-1461). The testcompounds inhibited the HMG CoA reductase enzyme.

B) In vivo:

a) Efficacy in genetic models:

Mutation in colonies of laboratory animals and different sensitivitiesto dietary regimens have made the development of animal models withnon-insulin dependent diabetes and hyperlipidemia associated withobesity and insulin resistance possible. Genetic models such as db/dband ob/ob (Diabetes, (1982) 31(1):1-6) mice and zucker fa/fa rats havebeen developed by the various laboratories for understanding thepathophysiology of disease and testing the efficacy of new antidiabeticcompounds (Diabetes, (1983) 32: 830-838; Annu. Rep. Sankyo Res. Lab.(1994). 46:1-57). The homozygous animals, C57 BL/KsJ-db/db micedeveloped by Jackson Laboratory, US, are obese, hyperglycemic,hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990)85:962-967), whereas heterozygous are lean and normoglycemic. In db/dbmodel, mouse progressively develops insulinopenia with age, a featurecommonly observed in late stages of human type II diabetes when bloodsugar levels are insufficiently controlled. The state of pancreas andits course vary according to the models. Since this model resembles thatof type II diabetes mellitus, the compounds of the present inventionwere tested for blood sugar and triglycerides lowering activities.

Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight rangeof 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animalhouse, were used in the experiment. The mice were provided with standardfeed (National Institute of Nutrition (NIN), Hyderabad, India) andacidified water, ad libitum. The animals having more than 350 mg/dlblood sugar were used for testing. The number of animals in each groupwas 4.

Test compounds were suspended on 0.25% carboxymethyl cellulose andadministered to test group at a dose of 0.1 mg to 30 mg/kg through oralgavage daily for 6 days. The control group received vehicle (dose 10mL/kg). On 6th day the blood samples were collected one hour afteradministration of test compounds/vehicle for assessing the biologicalactivity.

The random blood sugar and triglyceride levels were measured bycollecting blood (100 μl) through orbital sinus, using heparinisedcapillary in tubes containing EDTA which was centrifuged to obtainplasma. The plasma glucose and triglyceride levels were measuredspectrometrically, by glucose oxide and glycerol-3-PO₄oxidase/perioxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits,Hyderabad, India) methods respectively.

The blood sugar and triglycerides lowering activities of the testcompound was calculated according to the formula.

No adverse effects were observed for any of the mentioned compounds ofinvention in the above test.

Reduction in Blood Triglyceride Compound Dose (mg/kg) Glucose Level (%)Lowering (%) Example 14 3 52 61 Example 11 10  66 50 Example 28 1 40 40Example 30 1 44 05

The ob/ob mice were obtained at 5 weeks of age from Bomboltgard, Demarkand were used at 8 weeks of age. Zucker fa/fa fatty rats were obtainedfrom IffaCredo, France at 10 weeks of age and were used at 13 weeks ofage. The animals were maintained under 12 hour light and dark cycle at25±1° C. Animals were given standard laboratory chow (NIN, Hyderabad,India) and water, ad libitum (Fujiwara, T., Yoshioka, S., Yoshioka, T.,Ushiyama, I and Horikoshi, H. Characterization of new oral antidiabeticagent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats.Diabetes. 1988. 37:1549-1558).

The test compounds were administered at 0.1 to 30 mg/kg/day dose for 9days. The control animals received the vehicle (0.25%carboxymethylcellulose, dose 10 mL/kg) through oral gavage.

The blood samples wee collected in fed state 1 hour after drugadministration on 0 and 9 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride, glucose, free fatty acid, total cholesterol and insulinestimations. Measurements of plasma triglyceride, glucose, totalcholesterol were done using commercial kits (Dr. Reddy's Laboratory,Diagnostic Division, India). The plasma free fatty acid was measuredusing a commercial kit form Boehringer Mannheim, Germany. The plasmainsulin was measured using a RIA kit (BARC, India). The reduction ofvarious parameters examined are calculated according to the formula.

In ob/ob mice oral glucose tolerance test was performed after 9 daystreatment. Mice were fasted for 5 hrs and challenged with 3 gm/kg ofglucose orally. The blood samples were collected at 0, 15, 30, 60 and120 min for estimation of plasma glucose levels.

The experimental results from the db/db mice, ob/ob mice, Zucker fa/farats suggest that the novel compounds of the present invention alsopossess therapeutic utility as a prophylactic or regular treatment fordiabetes, obesity, cardiovascular disorders such as hypertension,hyperlipidaemia and other diseases; as it is known from the literaturethat such diseases are interrelated to each other.

Blood glucose level and triglycerides are also lowered at doses greaterthan 0.10 mg/kg. Normally, the quantum of reduction is dose dependentand plateaus at certain dose.

b) Cholesterol lowering activity in hypercholesterolemic rat models:

Male Sprague Dawley rats (NIN stock) were bred in DRF animal house.Animals were maintained under 12 hour light and dark cycle at 25±1° C.Rats of 180-200 gram body weight range were used for the experiment.Animals were made hypercholesterolemic by feeding 2% cholesterol and 1%sodium cholate mixed with standard laboratory chow [National Instituteof Nutrition (NIN), Hyderabad, India] for 6 days. Throughout theexperimental period the animals were maintained on the same diet (Petit,D., Bonnefis, M. T., Rey, C and Infante, R. Effects of ciprofibrate onliver lipids and lipoprotein synthesis in normo- and hyperlipidermicrats. Atherosclerosis. 1988. 74: 215-225).

The test compounds were administered orally at a dose 0.1 to 30mg/kg/day for 3 days. Control group was treated with vehicle alone(0.25% Carboxymethylcellulose; dose 10 mL/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 3 day of compound treatment. The blood wascollected from the retro-orbital sinus through heparinised capillary inEDTA containing tubes. After centrifugation, plasma sample was separatedfor total cholesterol, HDL and triglyceride estimations. Measurement ofplasma triglyceride, total cholesterol and HDL were done usingcommercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India).LDL and VLDL cholesterol were calculated from the data obtained fortotal cholesterol, HDL and triglyceride. The reduction of variousparameters examined are calculated according to the formula.

c) Plasma triglyceride and total cholesterol lowering activity in Swissalbino mice and Guinea pigs:

Male Swiss albino mice (SAM) and male Guinea pigs were obtained from NINand housed in DRF animal house. All these animals were maintained under12 hour light and dark cycle at 25±1° C. Animals were given standardlaboratory chow (NIN, Hyderabad, India) and water, al libitum. SAM of20-25 g body weight range and Guinea pigs of 500-700 g body weight rangewere used (Oliver, P., Plancke, M. O., Marzin, D., Clavey, V.,Sauzieres, J and Fruchart, J. C. Effects of fenofibrate, gemfibrozil andnicotinic acid on plasma lipoprotein levels in normal and hyperlipidemicmice. Atherosclerosis. 1988. 70: 107-114).

The test compounds were administered orally to Swiss albino mice at 0.3to 30 mg/kg/day dose for 6 days. Control mice were treated with vehicle(0.25% Carboxymethylcellulose; dose 10 mL/kg). The test compounds wereadministered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6days. Control animals were treated with vehicle (0.25%Carboxymethylcellulose; dose 5 mL/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 6 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride and total cholesterol (Wieland, O. Methods of Enzymaticanalysis. Bergermeyer, H. O. Ed., 1963, 211-214; Trinder, P. Ann. Clin.Biochem. 1969, 6 : 24-27). Measurement of plasma triglyceride, totalcholesterol and HDL were done using commercial kits (Dr. Reddy'sDiagnostic Division, Hyderabad, India).

Triglyceride Compound Dose (mg/kg) Lowering (%) Example 28 1 mg 22Example 30 1 mg 58 Example 25 1 mg  6

Formulae for calculation:

1. Percent reduction in Blood sugar/triglycerides/total cholesterol werecalculated according to the formula${{Percent}\quad {reduction}\quad (\%)} = {\left\lbrack {1 - \frac{{TT}/{OT}}{{TC}/{OC}}} \right\rbrack \times 100}$

OC=Zero day control group value

OT=Zero day treated group value

TC=Test day control group value

TT=Test day treated group value

2. LDL and VLDL cholesterol levels were calculated according to theformula:${{LDL}\quad {cholesterol}\quad {in}\quad \text{mg/dl}}\quad = {{{\left\lbrack {{{Total}\quad {cholesterol}} - {{HDL}\quad {cholesterol}} - \frac{Triglyceride}{5}} \right\rbrack \quad \text{mg/dl}{VLDL}\quad {cholesterol}\quad {in}\quad \text{mg/dl}} = {{\left\lbrack {{{Total}\quad {cholesterol}} - {{HDL}\quad {cholesterol}} - {{LDL}\quad {cholesterol}}} \right\rbrack \quad \text{mg/dl}}}}}$

What is claimed is:
 1. A compound of formula (Ih)

where R¹, R², R³, and R⁴ are the same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonicacid or its derivatives; the ring A fused to the ring containing X and Nrepresents a 5 or 6 membered cyclic structure containing carbon atoms,which optionally contains one or more heteroatoms selected from oxygen,sulfur or nitrogen atoms, which optionally may be substituted; the ringA is saturated or contains one or more double bonds or is an aromaticmoiety; X represents a heteroatom selected from oxygen, sulfur or NR⁹where R⁹ is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl,aryloxycarbonyl or aralkoxycarbonyl groups; Ar represents anunsubstituted or substituted divalent single or fused aromatic orheterocyclic group; R⁵ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl or unsubstituted or substituted aralkyl group orforms a bond together with the adjacent group R⁶, R⁶ representshydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl orunsubstituted or substituted aralkyl or R⁶ forms a bond together withR⁵; R⁸ represents hydrogen or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl orheteroaralkyl groups; n is an integer ranging from 1-4 and m is aninteger 0 or 1 or, polymorphs, tautomeric forms and stereoisomersthereof.
 2. A compound according to claim 1 wherein the substituents onR¹-R⁴ are selected from halogen, hydroxy, or nitro or unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aryloxy, aralkyl, aralkoxy, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl,alkylamino, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives.
 3. A compoundaccording to 1 wherein the cyclic structure A represents phenyl orpyridyl ring.
 4. A compound according to 1 wherein Ar representsunsubstituted or substituted divalent phenylene, naphthylene, pyridyl,quinolinyl, benzofuryl, benzopyranyl, benzoxazolyl, benzothiazolyl,indolyl, indolinyl, azaindolyl, azainolinyl, indenyl, dihydrobenzofuryl,dihydrobenzopyranyl or pyrazolyl group.
 5. A compound according to claim4 wherein the substituents on the group represented by Ar are selectedfrom linear or branched optionally halogenated (C₁-C₆)alkyl, optionallyhalogenated (C₁-C₃)alkoxy, halogen, acyl, amino, acylamino, thio,carboxylic acid and sulfonic acids and their derivatives.
 6. A compoundaccording to 1 wherein when m=0, Ar represents a divalent benzofuranyl,benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl ordihydrobenzopyranyl group.
 7. A compound according to 1 wherein whenm=1, Ar presents divalent phenylene, naphthylene, pyridyl, quinolinyl,benzofurnyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl,azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl,dihydrobenzopyranyl or pyrazolyl groups.
 8. A process for thepreparation of compound of formula (Ih) defined in claim 1 whichcomprises a) reacting a compound of formula (IIIe)

where L¹ is a leaving group and all other symbols are as defined abovewith a compound of formula (Io)

where R⁶ is hydrogen and all symbols are as defined above, to yield acompound of formula (In)

where all symbols are as defined above, and b) reacting a compound offormula (In) obtained above, with an appropriate diazotizing agent.